Identification of HIV inhibitors guided by free energy perturbation calculations.

摘要: Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact being felt in drug discovery. A review computer-aided anti-HIV efforts employing FEP calculations provided here describes early recent successes design human immunodeficiency virus type 1 (HIV-1) protease non-nucleoside reverse transcriptase In addition, our ongoing work developing optimizing leads small molecule inhibitors cyclophilin (CypA) highlighted as an update on current capabilities field. CypA has been shown aid HIV-1 replication by catalyzing cis/trans isomerization conserved Gly-Pro motif Nterminal domain capsid (CA) protein. absence functional CypA, e.g., addition inhibitor such cyclosporine (CsA), reduced infectivity. Our simulations acylurea-based 1-indanylketone-based have determined their nanomolar micromolar binding affinities, respectively, are tied ability stabilize Arg55 Asn102. structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed maximize these interactions. FEP-guided optimization, experimental synthesis, testing lead compounds toxicity inhibition wild-type CA mutants demonstrated dose-dependent infection two cell lines. While modest compared CsA, results encouraging.