title: Molecular dynamics and free energy studies on the wild-type and mutated HIV-1 protease complexed with four approved drugs: mechanism of binding and drug resistance.
abstract: The current strategy to improve the quality of life of Human Immunodeficiency Virus (HIV) infected individuals through suppressing viral replication and maintaining the virus at low to undetectable levels is based on highly active antiretroviral therapy (HAART). Protease inhibitors are essential components of most HAART protocols and are often used as the first line of treatment. However, a considerable percentage of new HIV-1 infections are caused by viruses carrying antiretroviral drug-resistant mutations. In this paper molecular dynamics, docking simulations, and free energy analysis of mutated HIV protease complexes were used to estimate the influence of different drug resistance-associated mutations in lopinavir, amprenavir, saquinavir, and atazanavir protease recognition. In agreement with virological and clinical data, the structural analysis showed that the single mutations V82A, I84V, and M46I are associated with higher energetic values for all analyzed complexes with respect to wild-type, indicating their decreased stability. Interestingly, in atazanavir complexes, in the presence of the L76V substitution, the drug revealed a more productive binding affinity, in agreement with hypersusceptibility data.
authors.affiliation: Laboratorio di Chimica Farmaceutica Computazionale-Dipartimento di Scienze Farmacobiologiche, Università Magna Graecia di Catanzaro, Campus Universitario, Viale Europa, 88100 Catanzaro, Italy. alcaro@unicz.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Anna
authors.initials: A
authors.lastname: Artese
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
authors.forename: Tobias
authors.initials: T
authors.lastname: Sing
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
mesh_terms: D003198:Computer Simulation; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1