Abstract
A computational study has been performed on a series of 55 compounds having (S)-N-(3-(N-(cyclopean- tylmethyl)substituted-phenylsulfonamido)-2-hydroxypropyl)acetamide backbone as HIV-1 protease inhibitors. Various combinations of these specific inhibitors fragments were formed by breaking them at central alicyclic single bonds, while retaining the core. Standard Topomer 3D models were automatically constructed for each fragment, and a set of steric and electrostatic fields was generated for each set of topomers. The models generated showed r2 of 0.811 and crossvalidated r2 (q2) of 0.608. The other method used were Quasar and Raptor based on receptor-modelling concept (6D-QSAR) and this explicitly allows for the simulation of the induced fit, that yielded r2 of 0.574, cross-validated r2 (q2) of 0.504 and predictive r2 (q2) of 0.895 averaged over 200 models. This study has suggested the various type of substituent that can be attached to the core. The information obtained from these 3-D contour maps can be used for the design of amprenavir analogs possessing better protease inhibitory activity.
Highlights
Replication of the HIV virus requires processing of the proteins encoded by the gag and gag-pol genes by a virally encoded aspartyl protease (HIV-1 protease) [1,2,3]
The other method used were Quasar and Raptor based on receptor-modelling concept (6D-QSAR) and this explicitly allows for the simulation of the induced fit, that yielded r2 of 0.574, cross-validated r2 (q2) of 0.504 and predictive r2 (p2) of 0.895 averaged over 200 models
Progress in the treatment of acquired immunodeficiency syndrome (AIDS) leading to an active therapy has been slow, but recent results with new AIDS drugs, notably the HIV-1 protease inhibitors (PI), allow for cautious optimism
Summary
Replication of the HIV virus requires processing of the proteins encoded by the gag and gag-pol genes by a virally encoded aspartyl protease (HIV-1 protease) [1,2,3]. Inhibition of HIV-1 protease offers an attractive target for the treatment of acquired immunodeficiency syndrome (AIDS) [4,5,6,7,8,9]. Inhibition of HIV protease is a target for drug design in a number of laboratories which has become a strategically important and therapeutically viable approach toward the control of HIV infection [10,11]. In 2009, ten protease inhibitors have reached the market where one protease inhibitor, amprenavir, was withdrawn from the market in 2004 since fosamprenavir, its prodrug proved superior in many aspects [12]. With increased frequency and duration of treatment, the rate of resistance toward antiretroviral agents, including PI s, has risen alarmingly, fueling the search for next-generation drugs with broad efficacy again-st PI-resistant mutants [13]
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