Screening And Study Of Potential Inhibitors Of SHMT2

Metabolic reprogramming is a significant sign of cancer cells,which is different from normal cell metabolism.This process is closely associated with the involvement of one-carbon units(1C).Serine hydroxymethyltransferase 2(SHMT2),which catalyzes the interconversion of serine and glycine,plays an indispensable role in promoting the one-carbon unit cycle during cancer cell metabolism.Multiple studies have demonstrated that inhibiting the high expression levels of SHMT2 can impede cancer progression.As such,SHMT2 has garnered significant interest as a promising anti-tumor drug target.However,no clinical drug has been developed to date,making it crucial to screen for inhibitors of this target.This study utilized virtual screening and free energy calculations to identify and investigate potential inhibitor molecules of SHMT2.This paper is divided into two parts.The first part includes a screening of all compounds in Chem Div using molecular docking,consensus scoring,and molecular clustering methods.This screening identified 38 molecules that show potential inhibitory activity against SHMT2.Molecular docking was conducted using Schr(?)dinger commercial software,followed by consensus scoring using both classical and machine learning-based scoring functions.The compounds identified through consensus scoring were then clustered based on their degree of structural similarity.Molecules with high scores were selected from clusters that contained representative structures.In the second part,molecular dynamics simulations and binding free energy calculations were performed for the complexes formed by 38 molecules with SHMT2 obtained after virtual screening.Lastly,six potential inhibitor molecules were selected,and their mechanism of binding to the SHMT2 protein was extensively studied.The reliability of the conclusions was confirmed by comparing the calculated results with the interaction pattern of the protein and ligand in the crystal structure.Our study revealed that the van der Waals energy generated between the A-chain residues LEU166 and ARG425,as well as the B-chain residues TYR105 and TYR106,and the benzene ring of the ligand,played a dominant role in the binding process.