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Updated: May 16, 2026
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System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
Published on: April 5, 2017
Identification of Selective Mtb-DHFR Inhibitors as Antitubercular Agents: A Fragment Merging Approach
Yash Kumar Gaur1, Milendra Kumar Turkar2, Aniket Nandi1
1Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, 142001, India.
Current Computer-Aided Drug Design
|May 15, 2026
Summary
Researchers developed a novel Fragment-Based Drug Design (FBDD) approach to identify selective inhibitors for M. tuberculosis Dihydrofolate reductase (Mtb-DHFR). Compound Z1 emerged as a promising lead, demonstrating high affinity and favorable drug-like properties for tuberculosis treatment.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Computational Biology
Background:
- Tuberculosis (TB) remains a leading global infectious disease, necessitating novel therapeutic strategies.
- Dihydrofolate reductase from M. tuberculosis (Mtb-DHFR) is a validated drug target essential for pathogen survival.
Purpose of the Study:
- To identify selective inhibitors of Mtb-DHFR using a Fragment-Based Drug Design (FBDD) approach.
- To develop novel antitubercular agents with improved selectivity over human DHFR.
Main Methods:
- A unique dual-grid FBDD strategy was employed, bifurcating the Mtb-DHFR active site.
- Virtual screening of a fragment library against dual grids, followed by focused library construction and screening.
- Cross-docking against human DHFR (hDHFR) was performed to assess selectivity.
Main Results:
- The FBDD approach yielded 258 fragment hits per sub-pocket, leading to 2000 full molecules.
- 20 compounds exhibited improved selectivity for Mtb-DHFR over hDHFR.
- Compound Z1 demonstrated high binding affinity, favorable ADMET properties, and stability via molecular dynamics simulations.
Conclusions:
- The dual-grid FBDD strategy effectively achieved selective Mtb-DHFR inhibition.
- Compound Z1 exhibits promising drug-like characteristics and stable binding, supporting its potential as a lead scaffold for antitubercular drug development.
