title: Computational studies of the resistance patterns of mutant HIV-1 aspartic proteases towards ABT-538 (ritonavir) and design of new derivatives.
abstract: Kinetic characterization and cross resistance pattern studies of HIV-1 aspartic protase (PR) inhibitors have shown that some mutations cause considerable reduction in inhibition efficiency. We have performed a computational study of the binding of ABT-538 (ritonavir) with wild type (wt) PR and 12 model mutant structures (R8Q, V321, M461, V82A, V82F, V821, I84V, M46I/V82F, M46I/I84V, V32I/I84V, V82F/I84V and V32I/K45I/F53L/A71V/I84V/L89M (6X)) for which inhibition data are available. Our computational studies indicate a significant correlation between computed complexation energies of ABT-538 with the modeled mutant enzyme structures and the corresponding experimental inhibition constants. By evaluating non-bonding interaction energies between the inhibitor and the mutant enzymes, we have carried out a mechanistic analysis to ascertain the reasons underlying the decrease in binding affinities. This analysis indicated that several residues in addition to the mutated residues contribute to the loss of binding. Taking these considerations into account, a number of new derivatives of ABT-538 were designed, so as to increase van der Waal's and hydrogen bonding interactions with selected mutants. A significant improvement in calculated complexation energies towards both mutant and wt PR structures was obtained for several of the redesigned analogues.
authors.affiliation: International Center for Science and High Technology, Area Science Park I-34102 Trieste, Italy.
authors.forename: Anil C
authors.initials: AC
authors.lastname: Nair
authors.forename: Irena
authors.initials: I
authors.lastname: Bonin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tossi
authors.forename: William J
authors.initials: WJ
authors.lastname: Wels
authors.forename: Stanislav
authors.initials: S
authors.lastname: Miertus
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004352:Drug Resistance, Microbial / Q000235:genetics*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D012015:Reference Standards; D019438:Ritonavir / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D016333:HIV Protease; D019438:Ritonavir