Ongoing · Chowdhury Lab, BITS Pilani Hyderabad
Structure-Based Virtual Screening of a Cryptic Allosteric Pocket in PfDHFR
Overview
Most antifolate drugs target the orthosteric folate-binding site of PfDHFR — the same site where resistance mutations accumulate. Building on the fitness-landscape and residue-network analyses of PfDHFR, this project develops a structure-based virtual screening pipeline targeting an allosteric, cryptic pocket identified from extensive molecular dynamics simulations of wild-type and resistant PfDHFR — a site less likely to already be under resistance-driven selection pressure.
The pipeline combines pocket detection across MD ensembles, molecular docking of candidate compound libraries, physics-based free-energy rescoring, and ADMET filtering to prioritise chemical starting points for antimalarial inhibitor development. It was developed as an application project for the Prognica Research Fellows Program 2026.
Key Highlights
- Pocket detection across molecular dynamics ensembles of multiple PfDHFR genotypes
- Targets a cryptic, allosteric pocket distinct from the orthosteric resistance-mutation site
- Structure-based docking with physics-based free-energy rescoring (MM-GBSA-style methods)
- ADMET-based filtering of candidate compounds
- Builds directly on the fitness-landscape and residue-network characterisation of PfDHFR
Researcher
Led by Danny Muzata in the Chowdhury Lab, Dept. of Biological Sciences, BITS Pilani Hyderabad Campus — part of the wider PfDHFR fitness-landscape research programme.