RESUMO
Docking is a computational technique that samples conformations of small molecules in protein binding sites; scoring functions are used to assess which of these conformations best complements the protein binding site. An evaluation of 10 docking programs and 37 scoring functions was conducted against eight proteins of seven protein types for three tasks: binding mode prediction, virtual screening for lead identification, and rank-ordering by affinity for lead optimization. All of the docking programs were able to generate ligand conformations similar to crystallographically determined protein/ligand complex structures for at least one of the targets. However, scoring functions were less successful at distinguishing the crystallographic conformation from the set of docked poses. Docking programs identified active compounds from a pharmaceutically relevant pool of decoy compounds; however, no single program performed well for all of the targets. For prediction of compound affinity, none of the docking programs or scoring functions made a useful prediction of ligand binding affinity.
Assuntos
Ligantes , Proteínas/química , Relação Quantitativa Estrutura-Atividade , Algoritmos , Sítios de Ligação , Desenho de Fármacos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , SoftwareRESUMO
Owing to the emergence of resistant virus, next generation non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) with improved drug resistance profiles have been developed to treat HIV infection. Crystal structures of HIV-1 RT complexed with benzophenones optimized for inhibition of HIV mutants that were resistant to the prototype benzophenone GF128590 indicate factors contributing to the resilience of later compounds in the series (GW4511, GW678248). Meta-substituents on the benzophenone A-ring had the designed effect of inducing better contacts with the conserved W229 while reducing aromatic stacking interactions with the highly mutable Y181 side chain, which unexpectedly adopted a "down" position. Up to four main-chain hydrogen bonds to the inhibitor also appear significant in contributing to resilience. Structures of mutant RTs (K103N, V106A/Y181C) with benzophenones showed only small rearrangements of the NNRTIs relative to wild-type. Hence, adaptation to a mutated NNRTI pocket by inhibitor rearrangement appears less significant for benzophenones than other next-generation NNRTIs.
Assuntos
Benzofenonas/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/farmacologia , Alcinos , Substituição de Aminoácidos , Benzofenonas/química , Benzoxazinas/química , Cristalografia por Raios X , Ciclopropanos , Desenho de Fármacos , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , Modelos Moleculares , Nevirapina/química , Nitrilas/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
A novel series of P1 modified HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and protease inhibitor-resistant viruses. Optimization of the P1 moiety resulted in compounds with femtomolar enzyme activities and cellular antiviral activities in the low nanomolar range culminating in the identification of clinical candidate GW0385.
Assuntos
Inibidores da Protease de HIV/farmacologia , Sulfonamidas/farmacologia , Inibidores da Protease de HIV/química , Estrutura Molecular , Sulfonamidas/químicaRESUMO
Optimization of P1-substituted pyrrolidinone based HIV protease inhibitors has yielded analogs with very potent antiviral activity.