Structural basis for the resilience of Darunavir (TMC114) resistance major flap mutations of HIV-1 protease

Interdisciplinary Sciences, Computational Life Sciences
Rituraj Purohit, Rao Sethumadhavan

Abstract

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...Continue Reading

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Citations

Feb 16, 2013·Cell Biochemistry and Biophysics·Ambuj KumarRituraj Purohit
Mar 16, 2013·Cell Biochemistry and Biophysics· Balu KRituraj Purohit
Apr 9, 2013·Cell Biochemistry and Biophysics·Ambuj KumarRituraj Purohit
Jan 8, 2013·Interdisciplinary Sciences, Computational Life Sciences·Nitin K SinghMuthukalingan Krishnan
Jan 8, 2013·Interdisciplinary Sciences, Computational Life Sciences·Gavish GulatiRituraj Purohit
Jun 7, 2013·Interdisciplinary Sciences, Computational Life Sciences·Ambuj KumarRituraj Purohit
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Jul 16, 2013·Cell Biochemistry and Biophysics·Ambuj KumarRituraj Purohit
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Jan 10, 2014·Interdisciplinary Sciences, Computational Life Sciences·Ambuj KumarRituraj Purohit
Jul 5, 2013·Cell Biochemistry and Biophysics·Balu Kamaraj, Rituraj Purohit
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Dec 10, 2015·Journal of Biomolecular Structure & Dynamics·Namrata KalsiRituraj Purohit
May 18, 2021·Journal of Biomolecular Structure & Dynamics·Pramod AvtiBikash Medhi

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