Integrated GC-MS Profiling and Multi-Scale Computational Analyses Identify Promising Phytochemicals Leads Targeting MAPK14 in Colorectal Cancer

Abstract

Purpose

Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide, with MAPK14 (p38 MAPK) playing an important role in tumor progression, immune evasion, cell proliferation, survival, and therapeutic resistance. This study aimed to evaluate the anti-colorectal cancer potential of two GC-MS-identified bioactive molecules against MAPK14 using integrated in silico approaches.

Methodology

The selected bioactive molecules were subjected to molecular docking against MAPK14 (PDB ID: 1OUY) using the GLIDE module of the Schrödinger suite, with a dihydropyrido-pyrimidine inhibitor as the control molecule. MMGBSA binding free-energy calculations were performed to assess binding affinity. Density functional theory (DFT) calculations, including HOMO–LUMO analysis and molecular electrostatic potential (MESP) mapping, were used to investigate electronic properties. In addition, in silico ADMET profiling and 200 ns molecular dynamics simulations were performed to evaluate pharmacokinetic properties, toxicity, structural stability, and dynamic behaviour. Principal component analysis (PCA) and free energy landscape (FEL) analyses were further employed to characterize conformational dynamics and stability.

Results

Both bioactive molecules showed favourable binding within the MAPK14 active site, stabilized by hydrogen-bonding and hydrophobic interactions involving key residues, including Lys53, Glu71, Met109, Gly110, and Asp168. MMGBSA analysis supported strong predicted binding affinities, with binding free-energy values below −30 kcal/mol. DFT and MESP analyses demonstrated favourable electronic characteristics and electrostatic complementarity with the binding site. ADMET profiling indicated favourable predicted oral bioavailability and low toxicity. Furthermore, 200 ns molecular dynamics simulations demonstrated stable phytochemical–MAPK14 complexes. PCA and FEL analyses further supported conformational stability, with dominant energy-favourable cluster basins observed in the FEL plots.

Conclusion

The integrated computational analyses suggest that the selected bioactive molecules possess favourable binding affinity, pharmacokinetic properties, and structural stability against MAPK14. These findings highlight their potential as anti-colorectal cancer leads and provide a basis for further experimental validation.