Search for Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase Using Chemical Similarity, Molecular Docking, and MM-GB/SA Scoring

Abstract

A virtual screening protocol has been applied to seek non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) and its K103N mutant. First, a chemical similarity search on the Maybridge library was performed using known NNRTIs as reference structures. The top-ranked molecules obtained from this procedure plus 26 known NNRTIs were then docked into the binding sites of the wild-type reverse transcriptase (HIV-RT) and its K103N variant (K103N-RT) using Glide 3.5. The top-ranked 100 compounds from the docking for both proteins were post-scored with a procedure using molecular mechanics and continuum solvation (MM-GB/SA). The validity of the virtual screening protocol was supported by (i) testing of the MM-GB/SA procedure, (ii) agreement between predicted and crystallographic binding poses, (iii) recovery of known potent NNRTIs at the top of both rankings, and (iv) identification of top-scoring library compounds that are close in structure to recently reported NNRTI HTS hits. However, purchase and assaying of selected top-scoring compounds from the library failed to yield active anti-HIV agents. Nevertheless, the highest-ranked database compound, S10087, was pursued as containing a potentially viable core. Subsequent synthesis and assaying of S10087 analogues proposed by further computational analysis yielded anti-HIV agents with EC50 values as low as 310 nM. Thus, with the aid of computational tools, it was possible to evolve a false positive into a true active.

N-Alkyl/aryl-4-(3-substituted-3-phenylpropyl)piperazine-1-carbothioamide as dual-action vaginal microbicides with reverse transcriptase inhibition

“…A hydrogen bond is formed between aliphatic side chain attached with thiourea group and the main-chain carbonyl oxygen of Lys101.A. A similar hydrogen bond to the main-chain carbonyl oxygen of Lys101.A has been observed for several other NNRTIs [18,19]. The compound 17 had similar binding mode as that of compound 12 with HIV-RT.…”

“…Within hydroxyl compounds (17e21) the preferred groups in thiourea at N 4 of piperazine were phenethyl (21) and butyl (17) against MTZ susceptible and phenethyl (21) and cyclohexyl (19) against resistant strain. When trifluoromethylphenoxy (22e26) group was present at position-3 of propanamine chain then phenethyl group in thiourea at N 4 of piperazine (26) susceptible to resistant strains while these compounds lost activity by 2e4 times only.…”

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

“…The past several years have been witness to many great successes in developing HIV-1 inhibitors with computer-aided approaches, e.g., virtual screening [41][42][43][44], molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) [45][46][47], molecular mechanics generalized Born surface area (MM-GB/SA) [48][49][50], and linear interaction energy (LIE) [51][52][53]. However, in keeping with the theme of this review, i.e., free energy perturbation calculations, not all studies can be highlighted.…”

“…FEP/MC guided optimization of a thiazole scaffold towards a low nM HIV-1 RT pyrimidine-based inhibitor [98][99][100]. FEP/MC guided optimization of an inactive oxadiazole scaffold towards a low nM HIV-1 RT inhibitor [48,70,101]. Transformation sequence used in the FEP simulations for the aryl 1-indanylketone-based compounds (2).…”

Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P&D de fármacos

“…Outrossim, esta técnica é útil na análise prévia de grandes bases de dados, permitindo a geração de coleções dirigidas para avaliações posteriores, experimentais ou computacionais. 15,17,41,45 …”