Identification of A Potential Inhibitor for Anticancer Target MTHFD2 by Consensus Docking and Molecular Dynamics

The bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) has been recognized as a promising anticancer drug target because it is overexpressed in various types of cancer and is associated with poor prognosis. In the present study, we aimed to discover potential inhibitors from the Enamine HTS library which consists of over one million compounds. A consensus docking-based virtual screening workflow was adopted and two hits, E96 and E41, were identified for being ranked in the top 5 in all docking programs used. To validate the virtual screening result, the binding modes of the two hits were visually inspected with reference to previously published inhibitors B01 and D56, and a similar pattern of binding was observed between the hits and established ligands, indicating the reliability of the docking protocol. The subsequent molecular dynamics simulation and a series of analyses including root mean square deviation, root mean square fluctuation, and radius of gyration reveal that E96 achieved a more stable binding to the receptor than E41. The binding free energy predicted by MM/GBSA calculation confirms E96s potential to be a potent inhibitor for the target MTHFD2 as it outperforms E41 and the established ligands. In conclusion, this computational study contributes to the drug discovery efforts for the anticancer drug target MTHFD2 by suggesting ligand E96 for further structure-based optimization and in vitro/vivo experimental validation.