Binding Interactions of Je-2147 (Normal vs Methylated) to HIV-1 Protease: A Molecular Dynamics Simulation Study for Drug Design Strategy.

Abstract

Human Immunodeficiency Virus (HIV) infection is a global public health problem with a higher rate of mortality. In current scenario, to treat HIV by presently marketed drugs in an effective manner, is a matter of concern. Due to the higher mutation rate of the HIV virus, the drug resistance has been an acute problem and a challenging issue for the treatment of HIV infected patients. HIV-1 protease (HIV-PR), one of the most vital enzymes of HIV and a crucial target for drug discovery, has been battered with numerous types of drugs. Regrettably, these actions have purely directed to mutations assisted drug resistance in HIV-PR. However, the molecular basis of drug resistance in HIV-PR is not precisely understood. JE-2147, an experimental inhibitor is prone to drug resistance and is explicit for I47V mutation. With mutation from Ile to Val in I47V mutant HIV-PR; a methyl group (-CH3) is lost from the sidechain of Ile creating a void space (near to P2’ position of JE-2147) directing the ligand to move freely in the active site region and thereby generating flexibility assisted drug resistance. The main objective of the present study is to uncover the binding mechanism of normal JE-2147 (JE2) and the methylated JE-2147 (JE2-CH3) in both WT and I47V mutant type to check the binding interactions between the two groups of inhibitors (normal vs Methylated). In the present study, we have chosen a methodology to comprehend the rational elucidation of the binding mechanism of JE2 and JE2-CH3 in WT and I47V mutant by merging molecular dynamics (MD) simulation, and MM-PBSA based free energy calculations. MM-PBSA based binding free energy calculations and residue decomposition analysis ratifies binding free energies crucial for the I47V mutant and WT complex as well. It is anticipated that the current study of comparison of WT and mutant complexes with the normal and methylated JE2 can pitch some valuable insights to the nature of I47V mutation effects, and the variance in binding affinity for the inhibitors JE2 and JE2-CH3 to design the significantly effective anti-HIV-PR drugs/inhibitors.

Keywords: HIV-1 protease, JE-2147, I47V mutation, MD simulation, anti-HIV-PR drugs