Title:A Step Towards Optimization of Amide-Linked Coumarin Pharmacophore: As an Anti-HIV Agent
Volume: 22
Issue: 5
Author(s): Harish Chandra Joshi, Vikas Kumar, Priyank Purohit*, Indra P. Pandey and Gaurav Joshi
Affiliation:
- School of Pharmacy, Graphic Era Hill
University, Dehradun, Uttarakhand, India
Keywords:
Reverse transcriptase inhibitors (RTI), QSAR, HIV integrase inhibitors, coumarins, protease inhibitors (PI), HIV/AIDS.
Abstract: The aim of the present investigation is to identify effective anti-HIV drugs through the
in-silico virtual screening of the coumarin pharmacophore with or without substituents. Virtual
screening started with target identification through computation docking and interactions, binding
affinity through molecular dynamics, and the ADMET profile through the use of various enzymes.
The target study suggests that the target is involved in various stages of HIV replication
and in determining the ways in which non-nucleoside reverse transcriptase inhibitors (RTIs) influence
it. The interaction pattern and simulation study conclude the specific affinity of coumarin
pharmacophore to the HIV's reverse transcriptase enzyme, especially 3HVT. Moreover, the amide
linkage worked as a synergistic bridge to provide more interaction to the pharmacophore. The
initial results led to the determination of 83 virtual amide-like molecules, which were screened
through docking and MD studies (100 ns) on the best-suited enzyme HIV's reverse transcriptase
enzyme, such as PDB ID “3HVT”. The virtual screening study revealed the high affinity of compounds
7d and 7e with the lowest IC50 values of 0.729 and 0.658 μM; moreover, their metabolism
pattern study, toxicity, and QED values in a range of 0.31-0.40 support a good drug candidate.
The two compounds were also synthesized and characterized for future in vitro and in vivo studies.
The in silico-based descriptor of compounds 7d and 7e indicates the potential future and provides
the best two molecules and their synthetic route for the development of a more effective
drug to combat HIV/AIDS epidemics.
