Rituraj Purohit and Rao Sethumadhavan
The HIV-1 protease enzyme is one of the prime and an utmost essentially important target towards the HIV therapy. However, one of the most complex mechanisms found in this enzyme is that, it produces resistance toward most of the drugs due to mutational changes, but still maintains activity with their natural substrates. This work focuses on mechanism of Darunavir resistance HIV-1 protease flap mutant I54M and I54L. To gain insight into why mutations confer such resistance, Docking analysis, binding energetics analysis and Molecular Dynamics simulations in explicit solvent were performed on drug resistant mutants and native HIV-1 protease. The flap mutation I54M and I54L lowers 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. In Darunavir resistance, the contribution of I54M mutant was more than I54L mutant. The results summarized in this paper emphasize the importance of shape complementarity and flexibility of binding residues in drug design.
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