Prediction of HIV-1 protease inhibitor resistance by Molecular Modeling Protocols (MMPs) using GenMol software.

This paper investigates the contribution of Molecular Modeling to (i) predict and (ii) understand more fundamentally HIV drug resistance. Based on a new automated GenMol module, these goals are approached by Molecular Modeling Protocols (MMPs), respectively, (i) the Molecular Modeling Phenotype Protocol (MMPP) and (ii) the Molecular Modeling Phenotype-Genotype Protocol (MMGPP). Section 2 recalls clinical practice with a reference case study and Section 3 presents atomistic simulation tools. Section 4 is the heart of the paper. In Section 4.1, MMPP drug resistance prediction is based on correlations between fold resistances versus binding energies on 2959 HIV-1 complexes with 6 protease inhibitors. Based on a drug sensitivity twofold criterion, modeling prediction is able to replace long and costly phenotype tests. In Section 4.2, MMGPP enlightens drug resistance by investigating steric and energetic residues/inhibitor interaction. Section 5 gives a synthesis on modeling contribution to drug resistance prediction. In conclusion, the most promising trend consists of MMP automats that are able to suggest a real time diagnosis taking into account the history of each patient, to enrich databases and to develop therapy strategy and new drugs.