Abstract
3,4,5-Trisubstituted-1,2,4-4H-triazoles (TTs) have recently been identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Two series of triazoles have been studied, one of which was also screened against the Y188L mutant. A computational strategy based on molecular docking studies followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) has been used to elucidate the atomic details of the RT/TT interactions and to identify the most important features impacting the TT antiretroviral activity. Two 3D-QSAR CoMFA and CoMSIA models were derived, using the TT pEC50 values measured against wild-type (WT) HIV-1 (model A) and the Y188L mutant form (model B), respectively, as the dependent variable. The final model A CoMSIA (r 2ncv = 0.97, r 2cv = 0.89, SEE = 0.314, and r 2pred = 0.82) and model B CoMSIA (r 2ncv = 0.91, r 2cv = 0.61, SEE = 0.236, and r 2pred = 0.73) analyses were more predictive. The results allowed us to obtain useful information for the design of new compounds with improved potency towards WT HIV-1 or that are potentially active against the Y188L mutant.
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Acknowledgments
This work was financially supported by the University of Genoa. Dr. B. Domenichini is gratefully acknowledged. E.C. was financially supported by a post-doc fellowship from Area Chimica, University of Genoa.
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Online Resource 1
Summary of CoMFA results for model A; summary of CoMSIA results for model A (DOC 37 kb)
Online Resource 2
Experimental and predicted pEC50 values of compounds 1, 3, 4, 6, 7, 10, 11, 13, 14, 16, 19, 22, 24–31, 33, 36, 39, 41, 45, 48–51, 53, 54, 57–60, 64–71, 77, 78, 80, 81, 84, 86–88, 90, 91, 94–96 (model A training set); experimental and predicted pEC50 values of compounds 2, 5, 8, 9, 12, 15, 17, 18, 20, 21, 23, 32, 34, 35, 37, 38, 40, 42–44, 46, 47, 52, 55, 56, 61–63, 72–76, 79, 82, 83, 85, 89, 92, 93, 97 (model A test set) (DOC 171 kb)
Online Resource 3
Model A CoMSIA hydrogen-bond acceptor polyhedra (a) and hydrogen bond donor polyhedra (b) are shown around compounds 15 (a representative of series 1 TTs, C is pink) and 83 (a representative of series 2 TTs, C is white), depicted in stick mode and colored by atom type. H-bond acceptor groups: magenta is favored; green is disfavored. H-bond donor groups: cyan is favored; purple is disfavored. Model B CoMSIA hydrogen-bond acceptor polyhedra (a) and hydrogen bond donor polyhedra (b) are shown around compounds 92, depicted in stick mode and colored by atom type. H-bond acceptor groups: magenta is favored; green is disfavored. H-bond donor groups: cyan is favored; purple is disfavored (DOC 706 kb)
Online Resource 4
Summary of CoMFA results for model B; summary of CoMSIA results for model B (DOC 112 kb)
Online Resource 5
Experimental and predicted pEC50 values of compounds 39–44, 47, 53–59, 61–64, 67, 68, 75–80, 82–92, 95 (model B training set); experimental and predicted pEC50 values of compounds 45, 46, 60, 65, 66, 81, 93, 94, 96 (model B test set) (DOC 138 kb)
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Cichero, E., Buffa, L. & Fossa, P. 3,4,5-Trisubstituted-1,2,4-4H-triazoles as WT and Y188L mutant HIV-1 non-nucleoside reverse transcriptase inhibitors: docking-based CoMFA and CoMSIA analyses. J Mol Model 17, 1537–1550 (2011). https://doi.org/10.1007/s00894-010-0857-7
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DOI: https://doi.org/10.1007/s00894-010-0857-7