Decomposing the energetic impact of drug resistant mutations in HIV-1 protease on binding DRV

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Drug Resistance, Viral; HIV Protease; HIV Protease Inhibitors; HIV-1; Sulfonamides


Biochemistry, Biophysics, and Structural Biology | Microbiology


Darunavir (DRV) is a high affinity (4.5x10(-12) M, DeltaG = -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.

DOI of Published Version



J Chem Theory Comput. 2010 Apr 13;6(4):1358-1368. Link to article on publisher's site

Journal/Book/Conference Title

Journal of chemical theory and computation

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Link to Article in PubMed

PubMed ID