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

被引:1
作者
Mitra, Rangan [1 ]
Kumar, Sandeep [1 ]
Ayyannan, Senthil Raja [1 ]
机构
[1] Banaras Hindu Univ, Indian Inst Technol, Dept Pharmaceut Engn & Technol, Pharmaceut Chem Res Lab 2, Varanasi, Uttar Pradesh, India
关键词
SHP2; pharmacophore query; ligand-based virtual screening; molecular docking; molecular dynamics simulation; synthesis; TYROSINE PHOSPHATASE; DESIGN; SCAFFOLD;
D O I
10.1080/07391102.2023.2291733
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu M) 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 mu M) against SHP2.
引用
收藏
页码:1352 / 1371
页数:20
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