title: Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir.
abstract: Molecular dynamics simulations are performed to investigate the dynamic properties of wild-type HIV-1 protease and its two multi-drug-resistant variants (Flap + (L10I/G48V/I54V/V82A) and Act (V82T/I84V)) as well as their binding with APV and DRV inhibitors. The hydrophobic interactions between flap and 80 s (80's) loop residues (mainly I50-I84' and I50'-I84) play an important role in maintaining the closed conformation of HIV-1 protease. The double mutation in Act variant weakens the hydrophobic interactions, leading to the transition from closed to semi-open conformation of apo Act. APV or DRV binds with HIV-1 protease via both hydrophobic and hydrogen bonding interactions. The hydrophobic interactions from the inhibitor is aimed to the residues of I50 (I50'), I84 (I84'), and V82 (V82') which create hydrophobic core clusters to further stabilize the closed conformation of flaps, and the hydrogen bonding interactions are mainly focused with the active site of HIV-1 protease. The combined change in the two kinds of protease-inhibitor interactions is correlated with the observed resistance mutations. The present study sheds light on the microscopic mechanism underlying the mutation effects on the dynamics of HIV-1 protease and the inhibition by APV and DRV, providing useful information to the design of more potent and effective HIV-1 protease inhibitors.
authors.affiliation: Drug Discovery and Design Center, ACS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Drug Discovery and Design Center, ACS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
authors.forename: Jinan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Drug Discovery and Design Center, ACS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shao
authors.affiliation: UCB Pharma, 216 Bath Road, Slough SL1 4EN, United Kingdom.
authors.forename: Jiye
authors.initials: J
authors.lastname: Shi
authors.affiliation: Drug Discovery and Design Center, ACS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
mesh_terms: D001665:Binding Sites; D002219:Carbamates / Q000737:chemistry / Q000378:metabolism*; D000069454:Darunavir / Q000737:chemistry / Q000378:metabolism*; D024882:Drug Resistance, Viral; D005663:Furans; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000069454:Darunavir