Title:Computational Exploration of Isatin Derivatives for InhA Inhibition in Tuberculosis: Molecular Docking, MD Simulations and ADMET Insights
Volume: 21
Issue: 2
Author(s): Vaishali Pavalbhai Patel, Rati Kailash Prasad Tripathi*Abhay Dharamsi
Affiliation:
- Department of Pharmaceutical Sciences, Sushruta School of Medical & Paramedical Sciences, Assam University (A Central University), Silchar, 788011, Assam, India
Keywords:
Tuberculosis, InhA or NADH-dependent enoyl-acyl carrier protein (ACP) reductase, isatin derivatives, molecular docking, conformational alignment studies, MD simulations, ADMET.
Abstract:
Background: Anti-tubercular drug discovery is a critical research area aimed at addressing
the global health burden imposed by Mycobacterium tuberculosis. Nowadays, computational
techniques have increased the likelihood of drug development compared to traditional,
labor-intensive, and time-consuming drug design approaches. The pivotal goal of drug design is
to identify compounds capable of selectively targeting protein, thereby disrupting its enzymatic
activity. InhA, or NADH-dependent enoyl-acyl carrier protein reductase, stands at the forefront
of targeted approaches in the battle against TB. Isatin derivatives have garnered interest for their
diverse pharmacological activities.
Objective: To identify novel isatin derivatives that could serve as potential chemical templates
for anti-TB drug discovery by targeting InhA.
Methods: The present work utilized various computational approaches, including molecular
docking, binding free energy calculations, and conformational alignment studies to investigate
the binding mode and interactions of carefully selected dataset of 88 isatin derivatives within
InhA active site. Study also employed MD simulations of the most promising molecule to check
the stability of the protein-ligand complex and in-silico ADMET profiling of the top compounds
to predict their pharmacokinetic and toxicity properties.
Results: Results provided insights into the structural features contributing to InhA inhibition,
assessing overall drug-like characteristics of isatin derivatives and identified compound 48
(BA= -10.4 kcal mol-1) with potential for further optimization. MD simulation analysis revealed
that compound 48 binds firmly within the InhA protein, exhibiting minimal conformational
fluctuations and enhanced stability.
Conclusion: Considering the aforementioned, isatin derivatives represents a novel framework
for creating targeted InhA inhibitors during anti-TB therapy. However, experimental validations
and in-depth analyses are crucial to confirm efficacy and safety of these derivatives as potential
InhA inhibitors for TB treatment.
