The primary focus of my doctoral thesis is to unravel the molecular mechanism of action and inhibition of HIV-1 protease (HIVPR), a key enzyme in the maturation of human immuno deficiency virus. Inhibiting this enzyme prevents the viral maturation, thus, making it one of the prime targets to combat AIDS. The thesis involves detailed investigations to explore the role of the inherent electric field in protease active site in substrate and drug binding, the mechanism of HIVPR dimerization, and the mechanism of irreversible inhibition of this enzyme by certain epoxide molecules. The electrostatic asymmetry found in the HIVPR active site led us to conclude that introducing the electrostatic component along with optimal fitting of the small molecules at protease binding pocket could aid in designing promising inhibitors against drug-resistant HIVPR variants [1]. Our suggested two-step process of HIVPR dimerization and the mechanism of dimerization inhibition by darunavir could accelerate the structure-based design of protease dimerization inhibitors. The epoxide ring opening in the enzyme followed a two-step mechanism with the formation of an oxyanion intermediate, stabilized by a set of water molecules in the protein active site [2]. These water molecules by virtue of low-barrier hydrogen bonds with the epoxide ring plays a co-catalytic role [3]. We believe these novel findings would offer new strategies to design better competitive, dimerization and irreversible HIV protease inhibitors.


patients.
Publications:

[1] Mohd Ahsan, Chinmai Pindi, and Sanjib Senapati “Electrostatics Plays a Crucial Role in HIV-1 Protease Substrate Binding, Drugs Fail to Take the Advantage” Biochemistry, 59, 3316-3331, 2020.

[2] Mohd Ahsan and Sanjib Senapati “Water Plays a Co-catalytic Role in Epoxide Ring Opening Reaction in Aspartate Proteases: A QM/MM Study” Journal of Physical Chemistry B, 123, 7955-64, 2019.

[3] Mohd Ahsan Chinmai Pindi and Sanjib Senapati “Hydrogen Bonding Catalysis by Water in Epoxide Ring Opening Reaction” Journal of Molecular Modelling and Graphics, 105, 107894, 2021.