Discovery Of SHMT2 Inhibitor And Study Of Their Binding Mechanism

Mitochondrial serine hydroxymethyl transferase isoform 2(SHMT2)has attracted increasing attention as a pivotal catalyzing regulator of the serine/glycine pathway in the one-carbon metabolism of cancer cells.However,few inhibitors that target this potential anticancer target have been discovered,and there are currently no clinical drugs on the market or on-going clinical trials.In drug discovery,accurately predicting the binding free energy and quantitatively characterizing their target-inhibitor interactions by computational method are of great significance in guiding drug discovery.This thesis consists of two parts: first,we employed an alanine-scanninginteraction-entropy(AS-IE)method to quantitatively calculate the residue-specific binding free energy of 28 different SHMT2 inhibitors that originate from the same skeleton;second,a combination of virtual screening and AS-IE method has been used to discover inhibitors of SHMT2.Quantitatively decomposing the total binding energy to specific residue is the strongest advantage of alanine-scanning.Major contributing residues from SHMT2 and chemical groups from the inhibitors were identified,and the binding energy of each residue was quantitatively determined,revealing essential features of the proteininhibitor interaction.The calculated protein-ligand binding free energies are in good agreement with the experimental results and showed better correlation and smaller errors compared with those obtained using the conventional MM/GBSA and normal mode method.Molecular docking and virtual screening were used to discover potential inhibitors in the Specs library containing 210,000 compounds.Combined with prediction of binding free energy using the AS-IE method,28 compounds were selected and purchased for in vitro experimental verification.Finally,two hits with enzymatic and cellular activity were identified,and a series of hit optimization and theoretical predictions of binding energy were performed through theoretical analysis of SHMT2 binding mode.Our results demonstrate that combining AS-IE with virtual screening may greatly improve the efficiency of inhibitor discovery.