6. Molecular Modelling Analysis of The Metabolism of Nelfinavir

Sheila Srivastava* Kulina Singh, Ajaya Awasthi, Shalini Singh & Parul Srivastava

Chemical Laboratories, Feroze Gandhi College, Raebareli-229001,India

*Author for correspondence e-mail: she_ila72@yahoo.com

 
Abstract

Nelfinavir mesylate (NFV) is a potent HIV-1 protease inhibitor that is commonly used in combination with reverse transcriptase inhibitors in the treatment of HIV-infection in pregnant women. However, NFV therapy is associated with glucose intolerance, insulin resistance and new onset of diabetes mellitus. Pregnancy is also a risk factor for glucose intolerance. The two major metabolites of NFV following its oral administration are 3’-methoxy-4’-hydroxynelfinavir (M1) and hydroxy-t-butylamidenelfinavir (M8). M8 is 98% as active as the parent drug whereas M1 is only 20% active. Another metabolite is 3’,4’-dihydroxynelfinavir (M3). Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that NFV and the metabolites M1, M3 and M8 have large LUMO-HOMO energy differences ranging from 4.9 to 5.1 eV from DFT calculations, indicating that they all would be kinetically inert. Thus, although the molecular surfaces of NFV and its metabolites possess some electron-deficient regions so that they may be subject to nucleophilic attack by glutathione and nucleobases in DNA, their kinetic inertness suggests that the rates of such adverse reactions may be low unless speeded up enzymatically.

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