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Journal of Pharmacology and Toxicology

Year: 2007  |  Volume: 2  |  Issue: 4  |  Page No.: 359 - 365

Molecular Modelling Analysis of the Metabolism of Latanoprost

Fazlul Huq

Abstract

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.

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