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Articles by Fazlul Huq
Total Records ( 53 ) for Fazlul Huq
  Fazlul Huq
  Maraviroc (MVC) is a selective CCR5 antagonist with potent activity and favourable pharmacological properties against human immunodeficiency virus type 1 (HIV-1). Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MVC and its metabolites have large LUMO-HOMO energy differences ranging from 5.3 to 5.8 eV, indicating that the compounds would be kinetically inert. The molecular surfaces of all the compounds are found to abound in neutral regions so that they may be subject to lyophilic attacks. The surfaces are also found to possess some electron-rich and electron-deficient regions so that they may be subject to electrophilic and nucleophilic attacks as well. Nucleophilic attacks may be due to glutathione and nucleobases in DNA as a result of which depletion of glutathione and oxidation of nucleobases in DNA may occur. The former would induce oxidative stress and hence cellular toxicity whereas the latter would cause DNA damage. However, because of kinetic inertness of the molecules, the rates of such adverse reactions are expected to be low.
  Fazlul Huq
  In present study, molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations have been carried out to obtain information on relative toxicity of UDF and its metabolites. The results of the analyses show that UDF and its metabolites have LUMO-HOMO energy differences of the order of 4.1 to 4.2 eV so that the compounds would all be moderately inert kinetically. The molecular surfaces of UDF and NDUDF are found to abound in neutral green and electron-deficient blue regions so that they can be subject to lyophilic and nucleophilic attacks. The latter attack can be due to glutathione and nucleobases in DNA so that the two compounds may induce cellular toxicity due to glutathione depletion and DNA damage due to oxidation of nucleobases in DNA. The other two metaboltes UDFM1 and UDFM3 abound in electron-rich red and yellow regions so that they are more likely to be subject to electrophilic attacks and may very well act as antioxidants.
  Fazlul Huq and Hehad Al-Shuneigat
  Methadone (Met) is a synthetic opiate used for analgesis in patients and to treat opioid dependence. Maintenance treatment with Met has contributed to a drop in mortality, reduction in heroin use, decrease in criminal activity and improvement in social relationships, reduction in risk of HIV and hepatitis virus infection. Met is an opiate μ-receptor agonist. It is a chiral molecule that exists in (S)-Met and (R)-Met forms. Except in Germany, Met is therapeutically administered as a racemic mixture. (R)-Met has a higher affinity for the μ-opioid receptor and a longer plasma elimination half-life than (S)-Met. Met undergoes rapid metabolism almost exclusively in the liver by sequential N-demethylation followed by spontaneous cyclisation to form EDDP and EMDP followed by renal and faecal excretion. EDDP and EMDP do not display any analgesic activity. Cytochrome P450 enzymes CYP3AP, CYP2B6 and CYP2C19 are involved in the metabolism of methadone in human liver and intestine. After steady-state administration of Met, a large variation in the plasma (R)-Met to (S)-Met ratio is observed across a population suggesting that Met is metabolized stereoselectively in vivo. Whereas N-demethylation through CYP3AP is not stereo selective, CYP2B6 is found to metabolize (S)-methadone more rapidly than (R)-methadone while CYP2C19 does the reverse. Molecular modelling analyses show that the two enantiomers of methadone differ in their LUMO-HOMO energy separation and hence in their kinetic lability. In both the enantiomers, the centre of most negative electrostatic potential is found to lie close to the tertiary nitrogen, indicating that the position may be most susceptible to electrophilic attack.
  Fazlul Huq
  Fenbufen (FN) is an orally and parenterally effective NSAID, used in the treatment of rheumatoid arthritis and characterized by low water solubility, particularly at low pH. It is actually a pro-drug of [1,1’-biphenyl]-4-acetic acid (BPAA) formed in its metabolism. Like other NSAIDs it shows activity in humans as wells a wide variety of animals including mice, rats, guinea pigs and dogs. However, FN is also known to produce a high incidence of skin rash especially in women. In aerated solution FN was found to sensitize the formation of singlet oxygen indicating FN is a strong photodynamic agent. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that FN and its metabolites differ in their LUMO-HOMO energy differences indicating that they would differ in their kinetic ability. The molecular surface of the metabolite BPEN is found to abound most in electron-deficient regions so that BPEN is more likely to react with cellular antioxidant glutathione and nucleobases in DNA resulting in glutathione depletion and DNA damage respectively. Depletion of reduced form of glutathione will induce cellular toxicity by compromising the antioxidant status of the cell.
  Fazlul Huq
  Aniracetam (ACM) is a pyrrolidinone-type cognition enhancer that has been used in the treatment of behavioural and psychological symptoms of dementia following stroke and Alzheimer’s disease. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that both ACM and its major metabolites have LUMO-HOMO energy differences ranging from 4.89 to 7.4 eV, indicating that the compounds would all be kinetically inert with SD being the most inert and the parent drug being the least inert one. The molecular surface of ACM is found to posses significant amounts of electron-deficient regions so that it can react with cellular nucleophiles such as glutathione and nucleobases in DNA, thus causing depletion of glutathione and oxidation of nucleobases. The former would induce cellular toxicity due to oxidative stress and the latter would cause DNA damage. However, because ACM is expected to be to some extent kinetically inert, the rates of such adverse reaction are expected to be low unless speeded up enzymatically.
  Fazlul Huq
  In this study, molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) have been carried out for troglitazone (TGZ) and its metabolites with the aim of obtaining information on their relative toxicity. The results of the analyses show that TGZ and its metabolites have LUMO-HOMO energy differences ranging from 4.1 to 4.9 eV from DFT calculations except TGZQ which has much lower value of 2.69 eV. The values suggest although TGZ and most of its metabolites would be kinetically inert, the metabolite TGZQ would be highly labile. The molecular surfaces of TGZ and its metabolites are found to abound in neutral (green) and electron-rich (red and yellow) regions so that the compounds may undergo lyophilic and electrophilic attacks. TGZ and all its metabolites also possess some electron-deficient regions so that they may be subject to nucleophilic attacks by glutathione and nucleobases as well. However, the rates of such adverse reactions are expected to be low for TGZ and its metabolites except in the case of the highly labile metabolite TGZQ.
  Fazlul Huq
  Probucol (PBC) is a phenolic antioxidant that was once used as a lipid lowering agent. However, in addition to having moderate low density lipoprotein lowering ability, the drug is also found to significantly lower high density lipoprotein levels and cause QTc (corrected heart rate) prolongation. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that PBC has a much larger LUMO-HOMO energy difference than its major metabolite SPQ so that PBC would be more kinetically inert than SPQ. Whereas the molecular surface of PBC is found to possess significant amount of electron-rich (red and yellow) regions so that it can act as an antioxidant, that of SPQ is found to possess significant amount of electron-deficient (blue) regions so that it can react with cellular nucleophiles glutathione and nucleobases in DNA. Reaction with glutathione would induce cellular toxicity due to glutathione depletion whereas the oxidation of nucleobases would cause DNA damage.
  Fazlul Huq
  Anagrelide is an orally active imidazoquinazoline derivative used for the treatment of thrombocytosis in patients with chronic myeloproliferative disorders. AG is extensively metabolized by the liver into two major metabolites BCH24426 and RL603. AG and its active metabolite RL603 reversibly block the maturation of late-stage megakaryocytes in a dose-dependent manner, thus reducing platelet counts in patients with essential thrombocythaemia. The most common adverse effects associated with anagrelide are headache, palpitations, diarrhoea, asthenia, oedema, nausea, abdominal pain and dizziness. AG is not mutagenic and to date there is no evidence to suggest it is leukaemogenic. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that AG and its metabolites BCH24426 and RL603 have moderately large LUMO-HOMO energy differences so that neither is expected to be highly labile. The active metabolite RL603 has the largest LUMO-HOMO energy difference so that it would be most inert kinetically. Thus although the molecular surfaces of neither AG and its metabolites are found to have some electron-deficient (blue) regions so that they can react with glutathione and nucleobases in DNA, the rates of such adverse reactions are not expected to be significant.
  Fazlul Huq
  Naproxen (NAP) is a non-steroidal anti-inflammatory drug that has been widely used in the treatment of rheumatoid arthritis and osteoarthritis. Although NAP is considered to be safe, it has a number of side-effects including gastrointestinal toxicity, nephrotoxicity, jaundice and hepatotoxicity. The hypersensitive response of NAP is believed to be associated with hepatitic injury caused by the drug. It has been suggested that the electrophilic metabolites of NAP can cause depletion of cellular glutathione and thus compromising the antioxidant status of the cell and can also cause oxidation of nucleobases in DNA. Molecular modelling analyses based on molecular mechanics, semi-empirical and DFT (at B3LYP/6-31G* level) calculations show that NAP and all its metabolites are expected to be neither extremely inert kinetically nor highly labile. The presence of both electron-rich and electron-deficient regions on the surfaces of NAP and its metabolites indicates that they may be subject to both electrophilic and nucleophilic attacks. The latter means that they can react with cellular glutathione, causing its depletion and thus inducing cellular toxicity. However, the kinetic inertness of NAP and its metabolites means that the rates of such adverse reactions would be low.
  Fazlul Huq
  Naltrexone (NTX) is a potent opioid antagonist that has been used in the treatment of alcohol dependence and opioid addiction. In humans, it has a plasma half-life of 2-14 h and volume distribution of 15 L kg-1. NTX therapy is associated with a number of gastrointestinal adverse effects including abdominal pain, nausea and vomiting, thus limiting its clinical utility. A major disappointment has been the poor patience compliance with the therapy. Reasons for non-adherence include poor motivation, cognitive impairment and the adverse effects of the drug. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that NTX, NTXOL and HMNTXOL have high LUMO-HOMO energy differences so that they would be kinetically inert. The presence of electron-deficient regions on the molecular surface indicates that the compounds can react with cellular glutathione, thus causing glutathione depletion and hence oxidative stress. Comparable surface area and volume for NTX and NTXOL indicates that the two compounds can be substrates for the same binding sites in opioid receptors.
  Fazlul Huq
  Niclosamide is a restricted-use pesticide that has been successfully used for more than 40 years to control sea lampreys (Petromyzon marinus) in streams tributary to the Great Lakes. As the chemical is generally applied directly to waterways inhabited by fish, there is a potential for niclosamide residue to accumulate in fish muscle tissue. Niclosamide is also used to kill golden apple snail (Pomacea canaliculata) which is a major pest of rice. Despite its general use, niclosamide is found to be toxic to several aquatic organisms. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that niclosamide and its metabolites differ in their LUMO-HOMO energy differences and hence kinetic lability. TCFNA has the smallest LUMO-HOMO energy difference and hence the greatest reactivity. It has also a lower solubility in water and possibly a lower thermodynamic stability. These properties may make TCFNA to be a toxic and mutagenic metabolite.
  Fazlul Huq
  Modafinil (MDF) is a unique wake-promoting agent that may be used in a variety of conditions including narcolepsy, obstructive sleep apnea and shift work sleep disorder. The mechanism of action of MDF is believed to be different from those of CNS stimulants such as amphetamine or methylphenidate. The drug is primarily metabolized in the liver and eliminated mainly as metabolites in the urine. It is based largely on amide hydrolysis and to a smaller extent proceeds via cytochrome P450-mediated oxidative pathways. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MDF and all its metabolites have large LUMO-HOMO energy differences so that they would be kinetically inert. The molecular surfaces MDF and all its metabolites are found to have electron-deficient regions so that they may be subject to nucleophilic attacks such as those by glutathione and nucleobases in DNA. Reaction with glutathione induces cellular toxicity compromising the antioxidant status of the cell whereas oxidation of nucleobases in DNA causes DNA damage. The kinetic inertness of the molecules may however mean that the rates of such adverse reactions may not be significant.
  Fazlul Huq
  Adefovir dipivoxil (ADV) is an oral prodrug designed to enhance low intestinal absorption of the anti-viral agent adepovil (PMEA). The pivoxil moieties of ADV are rapidly cleaved to produce PMEA during absorption through the gut wall. After entry into the cell, PMEA is phosphorylated to produce ADMP which is further phosphorylated to form ADDP. The antiviral activity of the drug is based on the capacity of ADDP to preferentially inhibit viral DNA replication with relative sparing of host DNA synthesis. The dose-limiting toxicity of ADV is nephrotoxicity associated with high systemic exposure. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that ADV and its three metabolites PMEAA, ADMP and ADDP have large LUMO-HOMO energy differences so that they all would be kinetically inert. Thus, although the molecules have some electron-deficient regions on their surface so that they could potentially react with glutathione and nucleobases in DNA, the high kinetic inertness of the molecules is believed to provide protection against such adverse reactions.
  Fazlul Huq
  Chloroform is still widely used as a solvent in industrial processes and formed as a by-product during chlorination of water intended for human consumption and paper bleaching. The main public health concern from chloroform exposure lies in its carcinogenic potential as it has been found to induce liver cancer in mice and renal tumours in male rats. It is believed that chloroform-induced toxicity is due to its cytochrome P450-mediated bioactivation to reactive metabolites. The compound can be metabolized by two different pathways, one of which follows oxidative dechlorination leading to the formation of phosgene and the other follows a reductive pathway leading to the formation of a reactive free radical. Molecular modelling analyses provide support to the idea that some of the metabolites of chloroform are more toxic than the parent compound. The metabolite phosgene is found to have electron-deficient regions on its molecular surface so that it can react with cellular glutathione, thus compromising the antioxidant status of the cell.
  Fazlul Huq and J. Al-Shuneigat
  Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that the metabolite codeinone is more kinetically labile than the parent drug codeine and other metabolites and that it can be subject to nucleophilic attack due to the presence of electron-deficient regions on its molecular surface. This means that the metabolite can react with glutathione thus causing glutathione depletion and can also cause oxidation of nucleobases in DNA thus producing DNA damage. Depletion of glutathione induces oxidative stress as it compromises the anti-oxidant status of the cell.
  Fazlul Huq
  Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that there are both electron-rich and electron-deficient regions on the molecular surfaces of IBF and its metabolites so that they can be subject to both electrophilic and nucleophilic attacks. The latter attack means that they can react with cellular glutathione, thus causing glutathione depletion and hence oxidative stress, and can also cause oxidation of nucleobases in DNA and thus DNA damage. However, the large LUMO-HOMO energy differences observed for IBF and all its metabolites may mean that the rates of such adverse reactions may be low.
  Fazlul Huq
  Hydrazine is a simple nitrogen compound that is used extensively in the manufacture of several important industrial products including plastic blowing agents, growth retardants and pharmaceuticals and in rocket propellants. It is a toxic compound causing fatty liver and in some cases liver necrosis, CNS disturbances and tumours in various organs. It is remarkably stable even though it has high (positive) heat of formation. Molecular modelling analyses show that although the reaction in which hydrazine decomposes to nitrogen and hydrogen is spontaneous, the relatively large kinetic barrier imparts stability to hydrazine molecule. However, since the reaction is highly exothermic, once it starts, it would speed up quickly. The metabolites THOPC and pyruvate hydrazone have relatively low LUMO-HOMO differences indicating that the two compounds would be the most reactive metabolites of hydrazine and the presence of negatively charged regions on its surface indicates that the metabolite can be subject to electrophilic attack.
  Fazlul Huq
  Isoniazid is the cornerstone of therapy against tuberculosis which is a global health problem of increasing dimension. Isoniazid is metabolized in the liver by acetylation and hydroxylation. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that isoniazid and its metabolites differ to some extent in their solvation energy, surface charge distribution, dipole moment, thermodynamic stability and kinetic lability. The metabolites hydrazine and acetylhydrazine are believed to be responsible for isoniazid induced liver toxicity. However, the results of molecular modelling analyses show that both the metabolites are kinetically inert. It is possible that these are spontaneously converted to more reactive metabolites pyruvate hydrazone and 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid. The charged nature of the surface of isoniazid and its metabolites indicates that the compounds may interact with biomolecules electrically. It also explains why the molecules are soluble in water.
  Fazlul Huq and Zahed Hossain
  Tuberculosis is a global health problem of escalating proportions especially due to the prevalence of the acquired immunodeficiency syndrome (AIDS) that has greatly increased the incidence of the disease over the first few years. A commonly used front-line anti-tuberculosis drug is pyrazinamide (PZA) that causes dose-dependent hepatotoxicity, manifested by hepatocellular dysfunction. The exact of mechanism of action of PZA and that of its toxicity remain unclear. In vivo, PZA is metabolized in the liver to form the main metabolite pyrazinoic acid (PA) by enzymatic deamination. PA is oxidised by the action of xanthine oxidase (XO) to form 5-OH-PA which is the main excretory metabolite of PZA. PZA is also directly oxidised to form 5-OH-PZA by XO. A small amount of PU is produced by conjugation of PA with glycine. Molecular modelling analyses show that PZA and its metabolites may be subject to electrophilic attack at a number of sites including the two pyrazine ring nitrogens. Neither PZA nor any of its metabolites have very small HOMO-LUMO energy differences so that none is expected to be highly labile kinetically and none can be excluded from being the cause for the toxicity of PZA.
  Fazlul Huq
  Maprotiline (also known as Ludiomil) (MAP) is a tetracyclic antidepressant that is chemically and functionally similar to tricyclic antidepressants (TCAs). It is a selective norepinephrine (NE) re-uptake blocker. The side effects of MAP include: nausea, nervousness, increased sweating, cholinergic blockade, cardiac complications such as ventricular tachycardia and atrial fibrillation and allergic reactions. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MAP and all its metabolites have large LUMO-HOMO energy differences so that they would be kinetically and therefore less likely to react readily with biomolecules. However, their low solvation energy and hence high lipid solubility suggest that the compounds would have low clearance rate. It is suggested that the toxicity of MAP and its metabolites may be associated with their low clearance rate.
  Fazlul Huq
  Fentanyl (FT) is a synthetic μ-opioid receptor agonist, widely used for surgical analgesia and sedation. FT undergoes rapid and extensive hepatic biotransformation to metabolites that result from hydrolysis, N-delalkylation and hydroxylation reactions. The major metabolite is norfentanyl (NFT) formed from N-delakylation. CYP3A4 is responsible for the oxidative dealkylation of FT in the human liver suggesting that FT may be subject to drug interactions in vivo as numerous other therapeutic agents including nifedipine, lidocaine and paracetamol are metabolized by the same enzyme. The toxicity of FT may be in part due to CYP3A4*1B and CYP3A5*3 variant alleles, resulting into variation in FT metabolism. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that FT and all its metabolites have large LUMO-HOMO energy differences so that they would be kinetically inert. However, the molecular surfaces of FT, PAL and NFT are found to abound in electron-deficient regions so that they may be subject to nucleophilic attack by glutathione and nucleobases in DNA resulting into glutathione depletion and DNA damage, respectively. The kinetic inertness of the molecules means that the rates of such adverse reactions would be low unless the reactions are speeded up enzymatically.
  Fazlul Huq
  Latanoprost (LP) is a synthetic derivative of the natural prostaglandin PGF2α, used as an anti-glaucoma agent that is effective in various types of glaucoma and ocular hypertension. It reduces intraocular pressure mainly by increasing outflow of aqueous humor. Ocular side effects of LP include increase in length, number, colorization and thickness of eyelashes and hypertrichosis. LP also appears to aggravate epithelial herpes and increases the risk of recurrences of herpetic keratitis. Increased iris pigmentation occurs in at least 10% of hazel-eyed patients after treatment with LP. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that LP and its metabolites have large LUMO-HOMO energy differences so that the compounds would be kinetically inert. This means that although there are some electron-deficient regions on the molecular surfaces of LP and its metabolites so that they can be subject to nucleophilic attacks by glutathione and nucleobases in DNA, in actual fact, the rates of such adverse reactions may be low. Thus, LP and its metabolites may not cause oxidative stress and DNA damage resulting from their reactions with glutathione and nucleobases in DNA unless such reactions are speeded up enzymatically.
  Fazlul Huq
  Ceftiofur sodium (CF) is a third generation broad-spectrum cephalosphorin, that is active against both Gram-positive and Gram-negative pathogenic bacteria of veterinary importance and has been approved for subcutaneous treatment of certain respiratory diseases in cattle, horses, pigs, poultry and dogs. CF is rapidly metabolized to its active metabolite desfuroylceftiofur (DFC) and furoic acid (FA) after parenteral administration. DFC is further metabolized to disulfides such as desfuroylceftiofur dimer (DFC-D), desfuroylceftiofur cysteine disulfide (DFC-CYS) and desfuroylceftiofur glutathione (DFC-GS) and desfuroylcetiofur protein conjugate that may be playing a role in the activity and efficacy of CF. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that metabolite DFC-D has the lowest LUMO-HOMO energy difference so that it would be most reactive kinetically. CF and DFC are also expected to be significantly more labile than FA and DFC-CYS. The higher kinetic lability and the presence of electron-deficient regions on the molecular surfaces of DFC-D, CF and DFC mean that the compounds would react more readily with reduced form of glutathione and nucleobases in DNA. The depletion of glutathione level will induce cellular toxicity resulting from oxidative stress and oxidation of nucleobases in DNA will cause DNA damage. In actual fact, the effects of such adverse reactions may be lower in the case of most reactive metabolite DFC-D because of its much greater ease in excretion.
  Fazlul Huq
  Tolterodine is a new antimuscarinic drug used for the treatment of patients with overactive bladder presenting urinary frequency, urgency and urge incontinence. In vitro, TTD has high affinity and specificity for muscarinic receptors and shows selectivity for the urinary bladder over salivary glands in vivo. It is a weak base that is rapidly absorbed in humans and eliminated mainly by metabolism. Two oxidative metabolic pathways of TTD involve hydroxylation and N-dealkylation. Hydroxylation produces 5-HM-TTD and is catalysed by CYP2D6 while the N-dealkylation to produce ND-TTD from tolterodine and ND-5-HM-TTD from 5-HM-TTD is catalysed by CYP3A. Oxidation of 5-HM-TTD produces TTDA. Delakylation of TTDA produces ND-TTDA. The major portion of administered dose is excreted as TTDA and ND-TTDA. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TTD and its primary metabolite M1 have moderately large to large LUMO-HOMO energy differences so that they would be kinetically inert. Thus, although TTD and its metabolites have some electron-deficient regions on their molecular surfaces so that they could react with glutathione and nucleobases in DNA, the rates of such adverse reactions are expected to be low.
  Fazlul Huq
  Fosamax (FSM) and risedronate (RDT) are a second and a third generation aminobisphosphonate respectively that are approved for the prevention and treatment of osteoporosis in post-menopausal women and elderly men. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that RDT has a much larger LUMO-HOME energy difference than FMX so that it would be more inert kinetically than FMX. The molecular surface of FSM is found to abound more in electron-rich red and yellow regions than that of RDT so that FSM may be subject to electrophilic attack. This means that FSM can compete better than RDT, with phospholipids for the binding sites on the surface of the mucus gel layer, thus causing a much greater reduction in the protective hydrophobic barrier. The lower gastric irritating action of FSM and RDT at low pH may be explained as being due to partial neutralization of surface charge on the molecules as a result of association with readily available hydrogen ions. Also at low pH, hydrogen ion may displace sodium ion from FSM producing the acid form of the molecule that is found to have much lower negative charge on its molecular surface.
  Fazlul Huq
  Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TGS and its major metabolites MIM, MIMA, MIMAG, ODMTGS, TGSG1, TGSG2 and TGSG3 have LUMO-HOMO energy differences ranging from 4.4 to 5.0 eV from DFT calculations so that they all would be moderately inert kinetically. The molecular surfaces of TGS and its metabolites are found to abound in neutral (green) and electron-rich (red and yellow) regions so that the compounds may undergo lyophilic and electrophilic attacks. The molecular surface of none of the compounds is found to abound in electron-deficient (blue) regions so that the compounds may not react readily with cellular nucleophiles such as glutathione and nucleobases in DNA. This means that none of the compounds may cause significant oxidative stress associated with glutathione depletion or DNA damage associated with oxidation of nucleobases.
  Fazlul Huq
  In this study, molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations have been carried out to obtain insight into their toxicity. The results of the analyses show that LLZ, LCZ and BFZ have LUMO-HOMO energy differences ranging from 4.5 to 4.9 eV, indicating that the compounds would be moderately inert with BFZ being the most inert one. The molecular surfaces of all the compounds are found to possess significant amounts of positively charged electron-deficient regions so that they may be subject to nucleophilic attacks by glutathione and nucleobases in DNA, thus causing cellular toxicity due to glutathione depletion and DNA damage due to oxidation of nucleobases. However, because of kinetic inertness of the molecules, the rates of such adverse reactions are expected to be low.
  Fazlul Huq
  Thiabendazole (TBZ) is a broad-spectrum anthelmintic that is effective against gastrointestinal nematodes in ruminants and lungworms in sheep. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TBZ and its metabolites have moderately large LUMO-HOMO energy differences except 5K-TBZ which has a much smaller value. The results indicate that generally TBZ and its metabolites would be fairly inert kinetically except 5K-TBZ which would be highly labile. The molecular surfaces of TBZ and its metabolites are found to possess neutral (green) and negative (yellow and red) and some electron-deficient (blue) regions so that they may be subject to lyophilic, electrophilic and nucleophilic interactions. Terminal metabolite TBZ-5S is found to abound most in electron-rich negative regions so that it may be most subject to electrophilic attack whereas the most reactive metabolite 5K-TBZ is found to abound most in electron-deficient regions so that it can be most subject to nucleophilic attack. Nucleophilic attack to the electron-deficient sites may be due to glutathione and nucleobases in DNA resulting into glutathione depletion and oxidation of nucleobases. Depletion of glutathione depletion would induce oxidative stress and hence cellular toxicity whereas oxidation of nucleobases in DNA would cause DNA damage.
  Fazlul Huq
  In this study, molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations have been carried out to obtain information on the toxicity of mexiletine (MEX) and its metabolites. The results of the analyses show that MEX and its metabolites have moderately large to large LUMO-HOMO energy differences ranging from 5.4 to 6.4 eV indicating that the compounds would be inert kinetically, with the parent drug being most inert. The molecular surface of one of the metabolites namely HMMEX is found to possess significant amount of positively charged electron-deficient regions so that it may be subject to nucleophilic attacks by glutathione and nucleobases in DNA, thus causing cellular toxicity due to glutathione depletion and DNA damage due to oxidation of nucleobases. However, because of kinetic inertness of the molecule, the rate of such adverse reactions is expected to be low.
  Fazlul Huq
  Clofarabine (CLF) is a new purine nucleoside antimetabolite developed for the treatment of solid and hematologic tumours. In this study molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations have been carried out to gain information on the relative toxicity of CLF and its metabolites. The study shows that CLF and its metabolites have large LUMO-HOMO energy differences of the order 5.3 eV from DFT calculations, indicating that CLF and all its metabolites would be kinetically inert. The molecular surfaces of CLF and all its metabolites are found to possess significant amounts of electron-rich (yellow and red) and neutral (green) regions so that the compounds may be subject to electrophilic and lyophilic attacks. However, the molecular surfaces do not appear to abound in electron-deficient (blue) regions (although the presence may be significant in the case of CLF, 2CAD and CLFDP) so that the compounds generally may not react to any significant extent with cellular nucleophiles such as the reduced form of glutathione and nucleobases in DNA. This means that other factors besides glutathione depletion and DNA damage may be playing key role in toxicity of CLF and its metabolites.
  Fazlul Huq
  Eszopiclone (ESZ) is a recently introduced drug to treat insomnia. In this study, molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations have been carried out to obtain insight into toxicity of ESZ and its metabolites. The results of the study show that both ESZ and its metabolites NDMESZ and ESZNO have small LUMO-HOMO energy differences, indicating that the compounds would be kinetically labile with ESZNO being most reactive. The molecular surfaces of ESZ, NDMESZ and ESZNO are found to posses significant amounts of electron-deficient regions so that the compounds, especially ESZNO, can react readily with cellular nucleophiles such as glutathione and nucleobases in DNA thus causing depletion of glutathione and oxidation of nucleobases. The former would induce cellular toxicity due to oxidative stress and the latter would cause DNA damage associated with oxidation of nucleobases.
  Fazlul Huq
  Clotrimazole (CTZ; bispheny l (2-chlorophenyl)-methan)) is an N-substituted imidazole drug that is used therapeutically as a topical antifungal agent. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that both CTZ and its major metabolite 2-chlorophenybiphenylmethanol (2CLBPM) have LUMO-HOMO energy differences so that they would be kinetically inert. The molecular surface CTZ is found to abound in electron-deficient regions so that it can react with cellular nucleophiles such as glutathione and nucleobases in DNA thus causing depletion of glutathione and oxidation of nucleobases. The former would induce cellular toxicity due to oxidative stress and the latter would cause DNA damage. However, because of kinetic inertness of CTZ, the rates of such adverse reaction are expected to be low unless speeded up enzymatically.
  Fazlul Huq
  In this study, molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations have been carried out to investigate the relative stability of ETV and its metabolites with the aim of providing a better understanding of their relative toxicity. The results of the analyses show that both ETV and its major metabolites have LUMO-HOMO energy differences so that they would be kinetically inert. The molecular surface of ETV is found to posses neutral, electron-rich and electron-deficient regions so that the compounds may be subjected to lyophilic, electrophilic and nucelephilic attacks. Nucleophilic attacks can be due to cellular nucleophiles such as glutathione and nucleobases in DNA. However, because of the kinetic inertness of the molecules the rates of such adverse reactions are expected to be low so that ETV and its metabolites may not cause high toxicity.
  Fazlul Huq
  Venlafaxine (VEN) is a new phenylethylamine bicyclic antidepressant whose activity is due to inhibition of neuronal uptake of norepinephrine, serotonin and dopamine. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that VEN and its major metabolites have high LUMO-HOMO energy differences ranging from 5.0 to 5.7 eV, indicating that the compounds would all be kinetically inert. The molecular surface of neither VEN nor any of its metabolites is found to abound in electron-deficient regions so that the compounds may not react with cellular nucleophiles such as glutathione and nucleobases in DNA. This means the compounds may not induce cellular toxicity associated with glutathione depletion and DNA damage associated with oxidation of nucleobases.
  Fazlul Huq
  Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MET and its major metabolites have LUMO-HOMO energy differences ranging from 4.1 to 6.7 eV from DFT calculations, indicating that they would vary significantly in their kinetic inertness. The molecular surfaces of MET, MTU, MET-EPO and GLX are found to possess significant amounts of electron-deficient regions so that they can react with cellular nucleophiles such as glutathione and nucleobases in DNA, thus causing depletion of glutathione and oxidation of nucleobases. The former would induce cellular toxicity due to oxidative stress and the latter would cause DNA damage. The rates of such adverse reactions are expected to be significant for GLX which would be moderately labile kinetically. This means that the toxicity due to MET may be mediated via the formation of GLX although the parent drug itself may also be responsible for toxicity if the rates of its reactions with glutathione and nucleobases in DNA are speeded up enzymatically.
  Fazlul Huq
  Terbinafine (TBN) is an orally active allylamine derivative that has fungicidal activity against dermatocytes and many pathogenic fungi. The drug is extensively metabolized in humans with systemic clearance being dependent primarily on its biotransformation. The five most prominent metabolites found in plasma are N-desmethylterbinafine (DTBN), hydroxyterbinafine (HTBN), N-desmethylhydroxy- terbinafine (DHTBN), carboxyterbinafine (CTBN) and N-desmethylcarboxyterbinafine (DCTBN) that together account for 25% of the total urinary excretion. Four other metabolites are 1-naphthaldehyde (NAL), 1-naphthalenemethanol (NM), 1-naphthanoic acid (NA) and N-desmethylterbinafine aldehyde (DATBN). Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TBN and its metabolites have LUMO-HOMO energy differences ranging from 4.22 to 4.73 eV based on from DFT calculations. The values suggest neither TBN nor any of its metabolites would be highly reactive or extremely inert. The molecular surface of TBN and the metabolites DATBN, NAL and DTBN are found to have significant electron-deficient regions so that they may be subject to nucleophilic attack by glutathione and nucleobases in DNA. DATBN that has been implicated as a possible cause for toxicity of TBN is found to abound most in electron-deficient regions although it has a slightly higher LUMO-HOMO energy difference than NAL. Reaction with glutathione would cause glutathione depletion resulting into oxidative stress and therefore cellular toxicity whereas the oxidation of nucleobases in DNA would cause DNA damage.
  Fazlul Huq
  Zolpidem (ZP) is a new orally active sleep inducer belonging to the class of compounds known as imidazopyridine. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that parent drug and all its metabolites have moderately large LUMO-HOMO energy differences so that none is expected to be highly labile kinetically. The molecular surface of ZP is found to abound in electron-deficient regions so that it can react with cellular nucleophiles such as glutathione and nucleobases in DNA, thus inducing cellular toxicity and causing DNA damage respectively. However, because of kinetic inertness, the rates of such adverse reaction may be low unless speeded up enzymatically. Increased incidence of nausea and vomiting associated with higher doses of ZP may be due to the parent drug rather than any of its metabolites.
  Fazlul Huq
  Ramelteon (RMT) is an agonist of the melatonin receptor, used for treatment of insomnia. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that RMT and its metabolites RMTM1, RMTM2, RMTM3 and RMTM4 have moderately large to large LUMO-HOMO energy differences so that the compounds would be moderate to highly inert kinetically. In spite of its kinetic inertness, the metabolism of RMT takes place rapidly because of the involvement of enzymes. The molecular surfaces RMT and its metabolites are found to abound in neutral (green) and electron-rich (red and yellow) regions so that the compounds may be subject to both lyophilic and electrophilic attacks. The absence of any significant amounts of electron-deficient (blue) regions on the molecular surface means that the compounds may not react with cellular glutathione and nucleobases in DNA. This means that RMT and its metabolites may not induce cellular toxicity (associated with glutathione depletion) and may not also cause DNA damage (associated with oxidation of nucleobases in DNA). Rather, the compounds may act more like antioxidants.
  Fazlul Huq
  Ambroxol (AMB) is used to treat acute and chronic bronchitis, bronchiectasia and lung tuberculosis and possesses antioxidant properties. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that AMB and its metabolites DHTQ and DBABA have LUMO-HOMO energy differences of 5.11, 5.01 and 4.28 eV, respectively from DFT calculations. The values indicate that AMB and DHTQ would be significantly more inert kinetically than DBABA. The molecular surfaces of AMB, DHTQ and DBABA are found to abound in neutral green regions so that the compounds can undergo lyophilic attack. The molecular surfaces of the three compounds are also found to possess significant amounts of electron-rich (red and yellow) regions so that they may be subject to electrophilic attacks as well. However, the compounds may not undergo significant nucleophilic attacks as their molecular surfaces do not abound in electron-deficient regions. The presence of neutral and electron-rich regions may impart antioxidant properties to AMB and its metabolites.
  Fazlul Huq
  Toluene has been widely used as an organic solvent, ingredient of thinners, as a coating in the leather industry and in the synthesis of a number of chemicals. It is a common cause of neurotoxicity in people that intentionally and repetitively breather high concentrations of toluene over a long period of time. Recent investigations have shown that toluene may induce reproductive dysfunctions and cancer. However, little is known about the molecular mechanisms by which toluene elicits its toxic effects on male reproductive organs and carcinogenicity. Following exposure in humans, toluene is readily transformed into several metabolites including benzyl alcohol, ortho-, meta- and para-cresols. The main metabolic pathway involves its oxidation to benzyl alcohol which is further oxidised to benzoic acid via benzaldehyde and excreted in the urine as hippuric acid. Ortho-, meta- and para-cresols are formed as minor metabolites through the formation of epoxides although there is evidence for direct hydroxylation of aromatic ring. Ortho-cresol is further hydroxylated to form MHQ which on oxidation produces MBQ. Molecular modelling analyses based on molecular mechanics, semi-empirical and DFT calculations show that the most toxic metabolite of toluene namely MBQ has the smallest LUMO-HOMO energy difference and hence it will be most reactive kinetically. The presence of electron-rich and electron-deficient sites indicates that the metabolite may undergo both electrophilic and nucleophilic attacks, the latter providing an explanation as to why it can cause oxidative damage to DNA.
  Fazlul Huq
  Naphthalene is a bicyclic aromatic hydrocarbon widely used as an intermediate in chemical and plastics industry and in the manufacture of insecticides and fungicides. It is metabolized by microsomal enzymes to naphthols and dihydrodiols via the formation of an epoxide which has a very short half-life. Reactive metabolites of naphthalene can deplete glutathione and in the absence of sufficient glutathione, get covalently bound to tissue macromolecules. In this study, molecular modelling analyses based on molecular mechanics, semi-empirical and DFT calculations have been carried out to provide information on the relative stability of naphthalene and its metabolites, deemed to be useful in the understanding of naphthalene induced toxicity. The analyses show that although naphthalene has a low thermodynamic stability, the larger LUMO-HOMO energy difference makes it less labile kinetically and hence less toxic than its more labile metabolites. Although naphthalene-1,2-epoxide has the lowest thermodynamic stability, the larger LUMO-HOMO energy difference makes the epoxide also labile. Much lower LUMO-HOMO energy differences make the naphthoquinones more reactive and hence more toxic.
  Fazlul Huq and Deena Ababneh
  Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations using the programs Spartan `02 and HyperChem 7.0 show that glycolic acid has high thermodynamic stability and low kinetic lability so that the reaction in which glycolic acid is converted to glyoxylic acid is indeed rate-determining. The metabolite glyoxal has the lowest LUMO-HOMO energy difference that makes it most kinetically labile. The high kinetic lability and the presence of electron-deficient region on the molecular surface may make glyoxal the most toxic metabolite as it can cause depletion of cellular glutathione, thus compromising antioxidant status of the cell.
  Fazlul Huq
  Phenytoin (PHT, also known as Dilantin) is a broad-spectrum anticonvulsant that is widely used for the prevention and treatment of seizure disorders. However, it provokes skin rash in 5 to 10% patients and has been found to be teratogenic in various experimental animal species. Epidemiological and clinical studies indicate that women who have taken PHT during pregnancy have an increased risk of bearing a child with a congenital anomaly. The toxic side effects of PHT may result from its primary and secondary metabolites, rather than the parent drug. PHT is metabolised by cytochrome P450 enzymes (CYP2C9 and CYP2C19) primarily to inactive metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (4HPPH, in both R- and S-forms, accounting for about 80% of all metabolites). 4HPPH may be further metabolized to catechol that spontaneously oxidizes to semiquinone and quinone species that bind covalently with proteins. Other minor metabolites in man are: 5-(3-hydroxyphenyl)-5-phenylhydantoin (3HPPH) and 5-(3,4-dihydroxy-1, 5-cyclohexadiene-1-yl)-5-phenylhydantoin (DHD). Molecular modelling analyses show that PHT and most of its metabolites do not differ widely in their kinetic lability except Q and SQ which have much lower values. Q has the lowest HOMO-LUMO energy difference and is therefore considered to be most toxic. The differences in heats of formation suggest that Q may be thermodynamically unstable as well that may be subject to both electrophilic and nucleophilic attack.
  Fazlul Huq
  Mefenamic acid is a NSAID that is widely used in analgesia. However, its use has been implicated in several cases of nephrotoxicity including acute renal failure and tubulointestinal nephritis. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MFA and its metabolites have similar LUMO-HOMO energy differences except MFA-Glu which has a much smaller value. This means that MFA and its metabolites have similar kinetic lability except MFA-Glu which is much more labile. The high kinetic lability of MFA-Glu suggests that it may react with biomolecules such as intra- and extracellular proteins more readily. However, whether this binding manifests itself as being a cause of MFA-induced toxicity remains unclear and may be confusing since the acyl glucuronides are considered to be less toxic. It may be that the formation of acyl glucuronide reduces toxicity associated with the carboxylic group but introduces new ones due to its high reactivity. It is found that the metabolites if MFA have higher solvation energies than MFA so that they may be more readily excreted in the urine.
  Fazlul Huq
  Cocaine is one of the main alkaloids of Erythroxylum coca that has a long history of human use and abuse. Cocaine acts as a local anaesthetic and stimulant causing increased alertness and a sense of euphoria. Sustained abuse of cocaine as a recreational drug is widespread around the world. Cocaine abuse during pregnancy is of major concern in certain countries where pregnant women take several drugs along with cocaine because it is known that cocaine can cross placenta. Cocaine has been reported to cause toxicity mainly to cardiovascular system and to a lesser extent to the liver. Cocaine is extensively metabolised in humans so that only a small percentage is excreted unaltered in urine. Cocaine is metabolized in vivo to pharmacologically inactive metabolites ecgonine methyl ester (ECG), benzoylecgonine (BE) and ecgonine (ECG). Among the metabolites BE has six times longer half-life than cocaine. Norcocaine is a relatively minor metabolite in humans. Molecular modelling analyses show that among cocaine and its metabolites, the metabolite cocaine N-oxide has the lowest LUMO-HOMO energy difference indicating that it has the greatest kinetic lability. The surface of the metabolite is also found to abound in electron-deficient regions so that it can cause oxidation of reduced form of glutathione and that of nucleobases in DNA, thus compromising the antioxidant status of the cell and inducing damage to DNA.
  Fazlul Huq
  Paracetamol is probably the most versatile and widely used analgesic and antipyretic drug all over the world and is also one of the commonest means of committing suicide. In humans, high doses of paracetamol can cause hepatotoxicity and sometimes nephrotoxicity. The drug is metabolized by different hepatic pathways to produce metabolites paracetamol sulfate, paracetamol glucuronide, NAPQI, PLCC and PNALCC. of these paracetamol sulfate and paracetamol glucuronide form the largest proportion. The metabolic activation of aspirin is associated with the formation of NAPQI which is highly toxic but is normally detoxified by reaction with glutathione. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) show that among paracetamol and its metabolites, NAPQI has the highest kinetic lability, lower solubility in water and possibly lower thermodynamic stability.
  Fazlul Huq
  Irbesartan (IS) is a potent, long-acting receptor antagonist for the octapeptide angiotensin II (AII), having high selectivity for the AT1 subtype. AII accelerates the development of atherosclerosis by activating AII subtype 1 receptors that promote generation superoxide anion and cause oxidative stress, leading to activation of nuclear transcription factor and endothelial dysfunction. IS is used in the treatment of hypertension, diabetic nephropathy and heart failure. The drug is metabolized in animals and humans to give at least seven urinary metabolites (denoted as M1, M2, M3, M4, M5, M6 and M7) although it does not rely on biotransformation for its pharmacological effect. IS shows minimal potential for drug or food interactions. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that IS and its metabolites have moderately large LUMO-HOMO energy differences ranging from 5.0 to 5.2 eV from DFT calculations, indicating that IS and all its metabolites will be kinetically inert. Thus, although the molecules have some electron-deficient regions on their surface so that they could potentially react with glutathione and nucleobases in DNA, the high kinetic inertness of the molecules is believed to provide protection against such adverse reactions.
  Fazlul Huq
  Enoxacin (ENX) is an orally active fluorinated quinolone antimicrobial agent that has strong activity against both gram-positive and gram-negative bacteria. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that ENX and its metabolites have moderately large LUMO-HOMO energy differences so that neither ENX nor any its metabolites is expected to be extremely inert and highly labile. The molecular surfaces of the compounds are found to possess neutral (green) and negative (yellow and red) and electron-deficient (blue) regions so that they may be subject to lyophilic, electrophilic and nucleophilic interactions. Nucleophilic attack may be due to glutathione and nucleobases in DNA resulting into glutathione depletion and oxidation of nucleobases. Depletion of glutathione depletion would induce oxidative stress and hence cellular toxicity whereas oxidation of nucleobases in DNA would cause DNA damage. Some what higher reactivity of ENX coupled with the presence of a larger amount of electron-deficient regions may mean that the consequences of such adverse reactions would be greater in the case of the parent drug than in any of the metabolites.
  Fazlul Huq
  Meropenem (MER) is a new carbapenum antibiotic that is highly active in the treatment of a broad range of pathogenic infections including gram-positive and gram-negative bacteria. It is water-soluble and eliminated mainly by renal excretion, through both glomerular filtration and tubular secretion. MER is metabolized into open ring metabolite UK-1a which is also microbiologically active. In healthy volunteers, 70% of the administered dose is excreted as the unchanged drug and 20% as the metabolite UK-1a, in the urine. There is a significant reduction in renal excretory capacity for MER and its metabolite UK-1a in elderly subjects. Molecular modelling analyses based on molecular mechanics, semi-empirical and DFT calculations show that both MER and UK-1a have large LUMO-HOMO energy differences so that they would be kinetically inert. Also, neither MER nor UK-1a is found to abound in electron-deficient regions so that they would not readily react with glutathione and nucleobases in DNA. This may explain why the side-effects from MER-therapy are low.
  Fazlul Huq
  Zaleplon (ZAL) is a sleep inducing agent with a prompt onset of action. It is rapidly metabolized with 88% of the dose appearing in the urine (71%) and faces (17%) as metabolites. A number of products including M1, M2 and DDZAL are produced from ZAL. M2 is the major metabolite in man whereas DZAL and DDZAL are the major plasma metabolites in rat, mouse and dog. Both M1 and M2 can form glucuronides. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that among ZAL and its metabolites, DDZAL has the smallest LUMO-HOMO energy difference so that it would be most kinetically labile. The high kinetic lability and the presence of electron-deficient regions on the molecular surface would make DDZAL the most toxic metabolite as it would react readily with glutathione and nucleobases in DNA. Reaction with glutathione would cause glutathione depletion thus inducing oxidative stress whereas that with nucleobases in DNA would cauase DNA damage.
  Fazlul Huq
  Vinyl chloride is a highly toxic industrial chemical that is carcinogenic to both humans and experimental animals. It is a colourless explosive gas that is almost insoluble in water but highly soluble in fats and organic solvents. Vinyl chloride is metabolized primarily in the liver. It is believed that the human carcinogenic outcome of vinyl chloride results from its metabolic activation, catalysed by cytochrome P450 enzyme, followed by DNA binding of the reactive metabolites to form exocyclic ethanol adducts. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations indicate that the long persistence of vinyl chloride in the environment is due to kinetic inertness. Although chloroethylene oxide is kinetically inert, it is thermodynamically unstable and spontaneously rearranges to more reactive metabolite chloroacetaldehyde. Relatively small LUMO-HOMO energy differences suggest that S-formylmethylcysteine, S-acetylglutathione and N-acetyl-S-(2-hydroxyethyl)cysteine would be kinetically labile and could be quite toxic but are more easily eliminated because of greater solubility in water.
  Fazlul Huq
  Zebularine (ZEB) is a pyrimidinone ribinucleoside that is a potent inhibitor of DNA methyltransferases. The inhibition of DNA methylation by ZEB is believed to result from the formation of a covalent adduct between the enzyme and ZEB-substituted DNA. Based on both in vitro and in vivo activity in mammalian cells, ZEB has been proposed for clinical evaluation as an oral antitumor agent. The compound is quite stable with half-lives of 44 and 68 h at pH 1.0 and 2.0, respectively and shows no evidence of decomposition after more than a week at pH 5. At pH 7.4, the half-life is 508 h. It has been suggested that the enhanced chemical stability of ZEB is responsible for its oral activity. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that ZEB and all its metabolites have large LUMO-HOMO energy differences indicating that they will be kinetically inert, thus providing an explanation for the long half-lives at different physiologically relevant pHs. The high solvation energies of ZEB and its metabolites suggest that they can be easily excreted via the urine.
  Fazlul Huq
  Rasagiline (RSG) is a second-generation, selective and irreversible inhibitor of monoamine oxidase type B (MAO-B) developed for the treatment of Parkinson’s diseases. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that both RSG and its metabolite ADN have large LUMO-HOMO energy differences so that they would be kinetically inert. The molecular surfaces RSG and ADN are found to possess neutral, electron-deficient and negatively charged regions so that they may be subject to lyophilic, nucleophilic and electrophilic attacks. However, because of kinetic inertness of the molecules, the rates of the reactions including any adverse reactions with glutathione and nucleobases in DNA are expected to be low. This may explain why RSG and ADN have little side effects.
 
 
 
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