Exploring marine-derived compounds for MET signalling pathway inhibition in cancer: integrating virtual screening, ADME profiling and molecular dynamics investigations

Abstract

The MET signalling pathway regulates fundamental cellular processes such as growth, division, and survival. While essential for normal cell function, dysregulation of this pathway can contribute to cancer by triggering uncontrolled proliferation and metastasis. Targeting MET activity holds promise as an effective strategy for cancer therapy. Among potential sources of anti-cancer agents, marine organisms have gained attention. In this study, we screened 47,450 natural compounds derived from marine sources within the CMNPD database against the Met crystal structure. By employing HTVS, SP, and XP docking modes, we identified three compounds (CMNPD17595, CMNPD14026, and CMNPD19696) that outperformed a reference molecule in binding affinity to the Met structure. These compounds demonstrated desirable ADME properties. Molecular Dynamics (MD) simulations for 200 ns confirmed the stability of their interactions with Met. Our findings highlight CMNPD17595, CMNPD14026, and CMNPD19696 as potential inhibitors against Met-dependent cancers. Additionally, these compounds offer new avenues for drug development, leveraging their inhibitory effects on Met to combat carcinogenesis.