Decomposing the energetic impact of drug-resistant mutations: the example of HIV-1 protease-DRV binding
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Crystallography, X-Ray; Drug Resistance, Viral; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Molecular Dynamics Simulation; Mutation; Sulfonamides; Thermodynamics
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.