title: Prediction of HIV-1 protease inhibitor resistance by Molecular Modeling Protocols (MMPs) using GenMol software.
abstract: 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.
authors.affiliation: GCOM2, UMR-CNRS 6114, Faculté des Sciences de Luminy, Case 901, 13288 Marseille Cedex 9, France. pepe@luminy.univ-mrs.fr
authors.forename: G
authors.initials: G
authors.lastname: Pèpe
authors.forename: J
authors.initials: J
authors.lastname: Courcambeck
authors.forename: R
authors.initials: R
authors.lastname: Perbost
authors.forename: P
authors.initials: P
authors.lastname: Jouanna
authors.forename: P
authors.initials: P
authors.lastname: Halfon
mesh_terms: D024882:Drug Resistance, Viral / Q000187:drug effects; D005838:Genotype; D006678:HIV / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010641:Phenotype; D012984:Software
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1