Journal of Computer-Aided Molecular Design

, Volume 26, Issue 8, pp 907–919 | Cite as

Comprehensive model of wild-type and mutant HIV-1 reverse transciptases

  • Flavio Ballante
  • Ira Musmuca
  • Garland R. Marshall
  • Rino Ragno
Article

Abstract

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 pKi). 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.

Keywords

3-D–QSAR HIV-1 reverse transciptase Drug resistance NNRTI RT mutants Molecular modeling COMBINEr DABO inhibitors PLS 

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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Flavio Ballante
    • 1
  • Ira Musmuca
    • 1
  • Garland R. Marshall
    • 1
    • 2
  • Rino Ragno
    • 1
  1. 1.Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del FarmacoSapienza Università di RomaRomeItaly
  2. 2.Department of Biochemistry and Molecular BiophysicsWashington University School of MedicineSt. LouisUSA

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