title: Decomposing the energetic impact of drug-resistant mutations: the example of HIV-1 protease-DRV binding.
abstract: HIV-1 protease is a major drug target for AIDS therapy. With the appearance of drug-resistant HIV-1 protease variants, understanding the mechanism of drug resistance becomes critical for rational drug design. Computational methods can provide more details about inhibitor-protease binding than crystallography and isothermal titration calorimetry. The latest FDA-approved HIV-1 protease inhibitor is Darunavir (DRV). Herein, each DRV atom is evaluated by free energy component analysis for its contribution to the binding affinity with wild-type protease and ACT, a drug-resistant variant. This information can contribute to the rational design of new HIV-1 protease inhibitors.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Cai
authors.forename: Celia
authors.initials: C
authors.lastname: Schiffer
mesh_terms: D018360:Crystallography, X-Ray; D000069454:Darunavir; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics*; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics*; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000069454:Darunavir