title: Insights into saquinavir resistance in the G48V HIV-1 protease: quantum calculations and molecular dynamic simulations.
abstract: The spread of acquired immune deficiency syndrome has increasingly become a great concern owing largely to the failure of chemotherapies. The G48V is considered the key signature residue mutation of HIV-1 protease developing with saquinavir therapy. Molecular dynamics simulations of the wild-type and the G48V HIV-1 protease complexed with saquinavir were carried out to explore structure and interactions of the drug resistance. The molecular dynamics results combined with the quantum-based and molecular mechanics Poisson-Boltzmann surface area calculations indicated a monoprotonation took place on D25, one of the triad active site residues. The inhibitor binding of the triad residues and its interaction energy in the mutant were similar to those in the wild-type. The overall structure of both complexes is almost identical. However, the steric conflict of the substituted valine results in the conformational change of the P2 subsite and the disruption of hydrogen bonding between the -NH of the P2 subsite and the backbone -CO of the mutated residue. The magnitude of interaction energy changes was comparable to the experimental K(i) data. The designing for a new drug should consider a reduction of steric repulsion on P2 to enhance the activity toward this mutant strain.
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Kitiyaporn
authors.initials: K
authors.lastname: Wittayanarakul
authors.forename: Ornjira
authors.initials: O
authors.lastname: Aruksakunwong
authors.forename: Suwipa
authors.initials: S
authors.lastname: Saen-oon
authors.forename: Wasun
authors.initials: W
authors.lastname: Chantratita
authors.forename: Vudhichai
authors.initials: V
authors.lastname: Parasuk
authors.forename: Pornthep
authors.initials: P
authors.lastname: Sompornpisut
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D003198:Computer Simulation; D004351:Drug Resistance; D004789:Enzyme Activation; D016333:HIV Protease / Q000032:analysis / Q000737:chemistry* / Q000648:ultrastructure*; D017320:HIV Protease Inhibitors / Q000032:analysis / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D009038:Motion; D046912:Multiprotein Complexes / Q000032:analysis / Q000737:chemistry / Q000648:ultrastructure; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D011789:Quantum Theory; D019258:Saquinavir / Q000032:analysis / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D046912:Multiprotein Complexes; D016333:HIV Protease; D019258:Saquinavir