Comprehensive model of wild-type and mutant HIV-1 reverse transciptases
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An enhanced version of COMBINE that uses both ligand-based and structure-based alignment of ligands has been used to build a comprehensive 3-D QSAR model of wild-type HIV-1 reverse transcriptase and drug-resistant mutants. The COMBINEr model focused on 7 different RT enzymes complexed with just two HIV-RT inhibitors, niverapine (NVP) and efavirenz (EFV); therefore, 14 inhibitor/enzyme complexes comprised the training set. An external test set of chiral 2-(alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones (DABOs) was used to test predictability. The COMBINEr model MC4, although developed using only two inhibitors, predicted the experimental activities of the test set with an acceptable average absolute error of prediction (0.89 pK i). Most notably, the model was able to correctly predict the right eudismic ratio for two R/S pairs of DABO derivatives. The enhanced COMBINEr approach was developed using only software freely available to academics.
Keywords3-D–QSAR HIV-1 reverse transciptase Drug resistance NNRTI RT mutants Molecular modeling COMBINEr DABO inhibitors PLS
The authors thank the research group (Rotili et al. ) of Prof. Antonello Mai for sharing their data about the separation and activity of their DABO derivatives prior to publication. In addition, Garland R. Marshall acknowledges financial support from the Dipartimento di Chimica e Tecnologie del Farmaco, Facoltà di Farmacia e Medicina, Sapienza Università di Roma, which made his visiting professorship in Rome feasible.
- 4.Musmuca I, Caroli A, Mai A, Kaushik-Basu N, Arora P, Ragno R (2010) Combining 3-D quantitative structure-activity relationship with ligand based and structure based alignment procedures for in silico screening of new hepatitis C virus NS5B polymerase inhibitors. J Chem Inform Model 50:662–676CrossRefGoogle Scholar
- 5.Rotili D, Samuele A, Tarantino D, Ragno R, Musmuca I, Ballante F, Botta G, Morera L, Pierini M, Cirilli R, Nawrozkij MB, Gonzalez E, Clotet B, Artico M, Este JA, Maga G, Mai A (2012) 2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies. J Med Chem 55:3558–3562CrossRefGoogle Scholar
- 7.Samuele A, Facchini M, Rotili D, Mai A, Artico M, Armand-Ugon M, Este JA, Maga G (2008) Substrate-induced stable enzyme-inhibitor complex formation allows tight binding of novel 2-aminopyrimidin-4(3H)-ones to drug-resistant HIV-1 reverse transcriptase mutants. ChemMedChem 3:1412–1418CrossRefGoogle Scholar
- 10.Mai A, Sbardella G, Artico M, Ragno R, Massa S, Novellino E, Greco G, Lavecchia A, Musiu C, La Colla M, Murgioni C, La Colla P, Loddo R (2001) Structure-based design, synthesis, and biological evaluation of conformationally restricted novel 2-alkylthio-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4 (3H)-ones as non-nucleoside inhibitors of HIV-1 reverse transcriptase. J Med Chem 44:2544–2554CrossRefGoogle Scholar
- 11.Quaglia M, Mai A, Sbardella G, Artico M, Ragno R, Massa S, del Piano D, Setzu G, Doratiotto S, Cotichini V (2001) Chiral resolution and molecular modeling investigation of rac-2-cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methyl pyrimidin-4(3H)-one (MC-1047), a potent anti-HIV-1 reverse transcriptase agent of the DABO class. Chirality 13:75–80CrossRefGoogle Scholar
- 12.Ragno R, Mai A, Sbardella G, Artico M, Massa S, Musiu C, Mura M, Marturana F, Cadeddu A, La Colla P (2004) Computer-aided design, synthesis, and anti-HIV-1 activity in vitro of 2-alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones as novel potent non-nucleoside reverse transcriptase inhibitors, also active against the Y181C variant. J Med Chem 47:928–934CrossRefGoogle Scholar
- 15.Mevik B-H, Wehrens R (2007) The pls package: principal component and partial least squares regression in R. J Stat Softw 18(2):1–24Google Scholar
- 19.Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461Google Scholar
- 20.R-Development-Core-Team R: a language and environment for statistical computing. http://www.R-project.org
- 21.Ballante F, Ragno R (2012) 3-D QSAutogrid/R: an alternative procedure to build 3-D QSAR models. Methodologies and applications. J Chem Inf Model 52:1674–1685Google Scholar
- 26.Azijn H, Tirry I, Vingerhoets J, de Bethune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT (2010) TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother 54:718–727CrossRefGoogle Scholar