Schweinfurthiamide as a Promising Anticancer Agent: Molecular Docking, Dynamics, and ADMET Insights Targeting MTHFD2

Abstract

Cancer remains a significant global health challenge, necessitating the Discovery of new therapeutic agents to overcome resistance and enhance treatment efficacy. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), overexpressed in various cancers, has emerged as a promising molecular target. In this study, the natural alkaloid schweinfurthiamide, isolated from Asparagus flagellaris, was evaluated as a potential MTHFD2 inhibitor using comprehensive in silico techniques. This study provides the first computational evaluation of schweinfurthiamide, focusing on its potential inhibition of MTHFD2 through Molecular docking and 200 ns molecular dynamics (MD) simulations. Molecular docking revealed a binding free energy (ΔG_bind) of − 8.19 kcal/mol for schweinfurthiamide, comparable to DS44960156 (− 8.13 kcal/mol), with key hydrogen bonds formed at ARG43, ASN87, LYS88, and GLY310. 200 ns MD simulations demonstrated the structural stability of the schweinfurthiamide-MTHFD2 complex, supported by RMSD, RMSF, Rg, and hydrogen bond analyses, as well as advanced metrics including radial distribution function (RDF), isotropically distributed ensemble analysis (IDEA), dynamic cross-correlation maps (DCCM), and 3D principal component analysis (3D-PCA). MM-PBSA calculations revealed a binding energy of − 31.51 ± 0.11 kcal/mol, slightly more negative than DS44960156 (− 29.48 ± 0.11 kcal/mol), highlighting robust electrostatic and hydrophobic interactions. Drug-likeness and ADMET predictions confirmed schweinfurthiamide’s compliance with the Lipinski Rule, Pfizer Rule, and Golden Triangle, with favorable plasma protein binding (72.57%), higher fraction unbound (28.66%), and low metabolic liabilities, suggesting strong pharmacokinetic potential. These integrated findings demonstrate that schweinfurthiamide exhibits strong binding affinity, stability, and drug-like properties, supporting its role as a new MTHFD2 inhibitor with potential anticancer efficacy. Further in vitro and in vivo validation is necessary to confirm its therapeutic potential and clinical applicability.

Graphical Abstract