title: Computational Prediction of HIV-1 Resistance to Protease Inhibitors.
abstract: The development of mutations in HIV-1 protease (PR) hinders the activity of antiretroviral drugs, forcing changes in drug prescription. Most resistance assessments used to date rely on expert-based rules on predefined sets of stereotypical mutations; such an information-driven approach cannot capture new polymorphisms or be applied for new drugs. Computational modeling could provide a more general assessment of drug resistance and could be made available to clinicians through the Internet. We have created a protocol involving sequence comparison and all-atom protein-ligand induced fit simulations to predict resistance at the molecular level. We first compared our predictions with the experimentally determined IC50 values of darunavir, amprenavir, ritonavir, and indinavir from reference PR mutants displaying different resistance levels. We then performed analyses on a large set of variants harboring more than 10 mutations. Finally, several sequences from real patients were analyzed for amprenavir and darunavir. Our computational approach detected all of the genotype changes triggering high-level resistance, even those involving a large number of mutations.
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center , c/Jordi Girona 29, 08034 Barcelona, Spain.
authors.forename: Ali
authors.initials: A
authors.lastname: Hosseini
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center , c/Jordi Girona 29, 08034 Barcelona, Spain.|Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology , Baldiri i Reixac 8, 08028 Barcelona, Spain.
authors.forename: Andreu
authors.initials: A
authors.lastname: Alibés
authors.affiliation: IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol , 08916 Badalona, Catalonia, Spain.|Universitat Autònoma de Barcelona , 08193 Bellaterra, Catalonia, Spain.|Universitat de Vic - Universitat Central de Catalunya , 08500 Vic, Catalonia, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Noguera-Julian
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center , c/Jordi Girona 29, 08034 Barcelona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Gil
authors.affiliation: IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol , 08916 Badalona, Catalonia, Spain.|Universitat Autònoma de Barcelona , 08193 Bellaterra, Catalonia, Spain.|Universitat de Vic - Universitat Central de Catalunya , 08500 Vic, Catalonia, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Paredes
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center , c/Jordi Girona 29, 08034 Barcelona, Spain.
authors.forename: Robert
authors.initials: R
authors.lastname: Soliva
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center , c/Jordi Girona 29, 08034 Barcelona, Spain.|Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology , Baldiri i Reixac 8, 08028 Barcelona, Spain.|Departament de Bioquímica, Universitat de Barcelona , Avgda Diagona 647, 08029 Barcelona, Spain.
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center , c/Jordi Girona 29, 08034 Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats , Passeig Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Guallar
mesh_terms: D000595:Amino Acid Sequence; D002219:Carbamates / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods*; D000069454:Darunavir / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D024882:Drug Resistance, Viral / Q000187:drug effects*; D005663:Furans; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009154:Mutation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D016333:HIV Protease; D000069454:Darunavir