Structural basis for the resilience of Darunavir (TMC114) resistance major flap mutations of HIV-1 protease.
To understand the origin of the apparent low sensitivity to mutations exhibited by Darunavir, the binding energetics of this inhibitor to the HIV-1 protease was studied. Our research indicates that the observed effectiveness of Darunavir against the wild type HIV-1 protease is due to an extremely high affinity towards the wild-type and a relatively mild effect to the I50V and I54M mutations is due to low affinity towards the inhibitor. Good affinity of Darunavir accounts for the additive effects of well accommodation at binding site, good ligand-receptor electrostatic and van der waals energy while, the low susceptibility to I50V and I54M can be rationalized in terms of flexibility in the binding site residues that do not permit drug accommodation to the binding site distortions created by the mutation. The major flap mutations I50V and I54M lower the binding affinity of Darunavir by altering the position of binding site residues in 3D space. It decreases the electrostatic and van der waals interaction energy and further reduction in total receptor-ligand interaction energy. The results summarized in this paper emphasize the importance of shape complementarity and protein flexibility analysis of binding residual interactions in drug design. These data together with an interaction energy and flexibility analysis have established rigorous guidelines for the design of new and more powerful inhibitors. The principles learned from the HIV-1 protease can be applied to other design problems.