Computational Insights into 1,4-Naphthoquinones as Allosteric MEK1 Inhibitors for Cancer Therapy

MEK1 plays a critical role in cellular survival and proliferation. Its activity is tightly regulated, and its dysregulation may lead to various cancers. It is frequently targeted for therapeutic intervention. 1,4-Naphthoquinones, a natural compound class, have garnered increasing interest for their anticancer potential.

A comprehensive library of 1,4-naphthoquinones was obtained from the PubChem database. This library was subjected to virtual screening using molecular docking against the allosteric site of MEK1 kinase. Selection was based on DOCK scores and pose similarity to the native inhibitor BBM. Ten compounds were selected and analyzed in detail for binding affinity, binding poses, and molecular interactions. Molecular dynamics (MD) simulation was performed for the top candidate.

The ten shortlisted compounds exhibited strong binding affinities for MEK1. Key residues involved in binding, including Asp-190, Asp-208, Phe-209, Met-219, and Lys-97, were consistently engaged by the shortlisted compounds and the native inhibitor. MD simulation of the top compound confirmed its stable binding. Pose overlay revealed that similar scaffolds showed comparable binding energies and interactions. ADMET predictions were considered in hit prioritization.

Early enrichment of true positives over decoys strongly supports the screening protocol. The common key residues shared between the naphthoquinones and the native inhibitor suggest a similar inhibitory mechanism. ADMET-based predictions led to the identification of the five most promising candidates.

This study proposed ten 1,4-naphthoquinones as potential allosteric inhibitors of MEK1. After integrating DOCK scores, binding energy, and ADMET risk, five compounds emerged as the most promising. These results provide a computational foundation for further testing.