title: Decomposing the energetic impact of drug resistant mutations in HIV-1 protease on binding DRV.
abstract: Darunavir (DRV) is a high affinity (4.5×10(-12) M, ΔG = -15.2 kcal/mol) HIV-1 protease inhibitor. Two drug-resistant protease variants FLAP+ (L10I, G48V, I54V, V82A) and ACT (V82T, I84V) decrease the binding affinity with DRV by 1.0 kcal/mol and 1.6 kcal/mol respectively. In this study the absolute and relative binding free energies of DRV with wild-type protease, FLAP+ and ACT were calculated with MM-PB/GBSA and thermodynamic integration methods, respectively. Free energy decomposition elucidated that the mutations conferred resistance by distorting the active site of HIV-1 protease so that the residues that lost binding free energy were not limited to the sites of mutation. Specifically the bis-tetrahydrofuranylurethane moiety of DRV maintained interactions with the FLAP+ and ACT variants, whereas the 4 - amino phenyl group lost more binding free energy with the protease in the FLAP+ and ACT complexes than in the wild-type protease which could account for the majority of the loss in binding free energy. This suggested that replacement of the 4 - amino phenyl group might generate new inhibitors less susceptible to the drug resistant mutations.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Cai
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer