In silico structure-based design of a potent, mutation resilient, small peptide inhibitor of HIV-1 reverse...

A crucial step in the replication of HIV-1 is the conversion of its single-stranded RNA to double-stranded DNA, which is catalyzed by the virally encoded reverse transcriptase (RT). The latter is therefore a key target for the development of anti-HIV drugs. Currently approved anti-RT drugs fall into two main classes: (i). nucleoside analog inhibitors which are incorporated into the primer strand in their metabolically activated triphosphate forms, causing termination of DNA synthesis due to their 3'-deoxy configuration and (ii). the non-nucleoside inhibitors (NNIs), which are generally specific for HIV-1 RT and bind at an allosteric site approximately 10 A from the active site causing a displacement of the catalytic aspartate residues. The so-called "first generation" NNI drugs are generally susceptible to the effects of single-point mutations within RT, while more recent "second generation" NNIs, such as efavirenz, the carboxanilide UC-781 and certain quinoxalines demonstrate much greater resilience to mutations in RT. The crystal structures of the complexes of wild type and mutant RTs with first and second generation NNIs have shown that, for an inhibitor to be potent as well as mutation resilient, it should (i). make hydrogen bonds with the main chain of RT, (ii). have a large number of interactions with RT and (iii). have the ability to rearrange and adapt to a mutated NNI pocket. Based on the crystal structures of the complexes of wild type RT and Tyr188Cys mutant of RT with UC-781, we have designed a small peptide inhibitor. Docking results on this peptide using AutoDock3.0 and SYBYL 6.8.1 indicate that the peptide has a potency comparable to that of UC-781 with a retention of activity against the Tyr188Cys mutant RT. The proposed, small peptide is seen to possess all the desirable features of a potent and mutation resilient inhibitor and is hence a potential lead compound.