Identification of new small molecule allosteric SHP2 inhibitor through pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation studies, synthesis and in vitro evaluation

Src homology-2 (SH2) domain-containing phosphatase-2 (SHP2) is the first identified protooncogene and is a promising target for developing small molecule inhibitors as Cancer chemotherapeutic agents. Pharmacophore-based virtual screening (PBVS) is a pharmacoinformatics methodology that employs physicochemical knowhow of the chemical space into the dynamic environs of computational technology to extract virtual molecular hits that are precise and promising for a drug target. In the current study, PBVS has been applied on Enamine^TM Advanced Collection of 551,907 molecules by using a pharmacophore model developed upon SHP099 by Molecular Operating Environment (MOE) software to identify potential small molecule allosteric SHP2 inhibitors. Obtained 37 hits were further filtered through DruLiTo software for drug-likeness and PAINS remover which yielded 35 hits. These were subjected to molecular docking studies against the tunnel allosteric site of SHP2 (PDB ID: 5EHR) to screen them according to their binding affinity for the Enzyme. Top 5 molecules having highest binding affinity for 5EHR were passed through an ADMET prediction screening and the top 2 hits (ligands 111675 and 546656) with the most favourable ADMET profile were taken for post screening molecular docking and MD simulation studies. From the protein-ligand interaction pattern, conformational stability and energy parameters, ligand 111675 (SHP2 K_i = 0.118 µM) resulted as the most active molecule. Further, the synthesis and in vitro evaluation of the lead compound 111675 unveiled its potent inhibitory activity (IC₅₀ = 0.878 ± 0.008 µM) against SHP2.Communicated by Ramaswamy H. Sarma.

SHP2; ligand-based virtual screening; molecular docking; molecular dynamics simulation; pharmacophore query; synthesis.