Molecular Modelling Analysis of the Metabolism of Irbesartan
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.
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