title: Drug-resistant molecular mechanism of CRF01_AE HIV-1 protease due to V82F mutation.
abstract: Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the major targets of anti-AIDS drug discovery. The circulating recombinant form 01 A/E (CRF01_AE, abbreviated AE) subtype is one of the most common HIV-1 subtypes, which is infecting more humans and is expanding rapidly throughout the world. It is, therefore, necessary to develop inhibitors against subtype AE HIV-1 PR. In this work, we have performed computer simulation of subtype AE HIV-1 PR with the drugs lopinavir (LPV) and nelfinavir (NFV), and examined the mechanism of resistance of the V82F mutation of this protease against LPV both structurally and energetically. The V82F mutation at the active site results in a conformational change of 79's loop region and displacement of LPV from its proper binding site, and these changes lead to rotation of the side-chains of residues D25 and I50'. Consequently, the conformation of the binding cavity is deformed asymmetrically and some interactions between PR and LPV are destroyed. Additionally, by comparing the interactive mechanisms of LPV and NFV with HIV-1 PR we discovered that the presence of a dodecahydroisoquinoline ring at the P1' subsite, a [2-(2,6-dimethylphenoxy)acetyl]amino group at the P2' subsite, and an N2 atom at the P2 subsite could improve the binding affinity of the drug with AE HIV-1 PR. These findings are helpful for promising drug design.
authors.affiliation: Department of Bioscience and Biotechnology, School of Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, People's Republic of China. lxq785348@163.com
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Liu
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Xiu
authors.forename: Ce
authors.initials: C
authors.lastname: Hao
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000235:genetics* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D061466:Lopinavir; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019888:Nelfinavir / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D011744:Pyrimidinones / Q000378:metabolism / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D016333:HIV Protease; D019888:Nelfinavir