title: Revealing origin of decrease in potency of darunavir and amprenavir against HIV-2 relative to HIV-1 protease by molecular dynamics simulations.
abstract: Clinical inhibitors Darunavir (DRV) and Amprenavir (APV) are less effective on HIV-2 protease (PR2) than on HIV-1 protease (PR1). To identify molecular basis associated with the lower inhibition, molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations were performed to investigate the effectiveness of the PR1 inhibitors DRV and APV against PR1/PR2. The rank of predicted binding free energies agrees with the experimental determined one. Moreover, our results show that two inhibitors bind less strongly to PR2 than to PR1, again in agreement with the experimental findings. The decrease in binding free energies for PR2 relative to PR1 is found to arise from the reduction of the van der Waals interactions induced by the structural adjustment of the triple mutant V32I, I47V and V82I. This result is further supported by the difference between the van der Waals interactions of inhibitors with each residue in PR2 and in PR1. The results from the principle component analysis suggest that inhibitor binding tends to make the flaps of PR2 close and the one of PR1 open. We expect that this study can theoretically provide significant guidance and dynamics information for the design of potent dual inhibitors targeting PR1/PR2.
authors.affiliation: School of Science, Shandong Jiaotong University, Jinan 250357, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Science, Shandong Jiaotong University, Jinan 250357, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Liang
authors.affiliation: School of Science, Shandong Jiaotong University, Jinan 250357, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Science, Shandong Jiaotong University, Jinan 250357, China.
authors.forename: Changhong
authors.initials: C
authors.lastname: Yi
authors.affiliation: College of Physics and Electronics, Shandong Normal University, Jinan, 250014, China.
authors.forename: Shaolong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: College of Physics and Electronics, Shandong Normal University, Jinan, 250014, China.
authors.forename: Qinggang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D002219:Carbamates / Q000737:chemistry*; D020134:Catalytic Domain; D000069454:Darunavir; D024882:Drug Resistance, Viral; D005663:Furans; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology; D015498:HIV-2 / Q000201:enzymology; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013449:Sulfonamides / Q000737:chemistry*; 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; C065184:p16 protease, Human immunodeficiency virus 2; D000069454:Darunavir