Understanding Periperal Membrane Protein Interactions | BPS Thematic Meeting

Understanding Peripheral Membrane Protein Interactions: Structure, Dynamics, Function and Therapy

Poster Abstracts

20-POS Board 20 STRUCTURE-GUIDED DISCOVERY AND CHARACTERIZATION OF MAPK6 INHIBITORS FROM PHYTOCHEMICALS THROUGH DENSITY FUNCTIONAL

THEORY AND MICROSECOND MD SIMULATIONS Md Nayab Sulaimani ; Md. Imtaiyaz Hassan 1 ; Ravins Dohare 1 ;

1 Jamia millia islamia, centre for interdisciplinary reserach in basic sciences, New delhi, India Mitogen-activated protein kinase 6 (MAPK6/ERK3) has emerged as an unconventional kinase implicated in tumor growth, migration, and survival, making it a promising yet underexplored target for cancer therapeutics. Despite increasing evidence of its oncogenic role, no selective inhibitors of MAPK6 have been reported so far, leaving a critical gap in targeted therapy development. In this study, we employed an integrated structure-based drug discovery pipeline to identify and characterize potent small-molecule inhibitors of MAPK6. A curated library of 17,908 phytochemicals obtained from the IMPPAT 2.0 database (Indian Medicinal Plants, Phytochemistry and Therapeutics) was subjected to virtual screening and molecular docking, yielding 20 top candidates with high binding affinity toward the ATP-binding pocket. These compounds were further evaluated through physicochemical property assessment, ADMET profiling, PASS prediction, and interaction analysis. The most promising lead was subsequently investigated using density functional theory (DFT) calculations to elucidate its electronic properties and reactivity. To probe dynamic stability, MAPK6 and ligand-bound complexes were examined through an extensive 1 µs molecular dynamics (MD) simulation, followed by binding free energy estimation using the MM-PBSA method. Essential dynamics analysis provided additional insights into conformational flexibility and functional motions of MAPK6 upon inhibitor binding. Collectively, our integrative computational approach identified four natural product-derived hits, Candidine, Jervine, Glabrocoumarin and Artonin P with strong binding affinity, favorable pharmacological features, and high structural stability. This work bridges the knowledge gap in MAPK6-targeted therapy and offers valuable leads for experimental validation and rational design of first-in-class MAPK6 inhibitors for cancer therapeutics. Keywords: Virtual screening, molecular docking, DFT analysis, MD simulation, MMPBSA, cancer therapeutics, drug discovery.

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