Rong Liu, Liang Zou, Maoqi Wang, Yueyue He, Mao Shu
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Computational insights and activity evaluation of novel SHP-2 inhibitors for targeting type 2 diabetes mellitus.
Protein-tyrosine phosphatase-2 (SHP-2) has become a new target in the study of type 2 diabetes mellitus (T2DM). Currently, there are no marketed drugs targeting SHP-2 to study T2DM caused by insulin resistance. Therefore, this study screened out SHP-2 inhibitors with potential inhibitory activity from 2 million compounds, combined with ADME/T, Lipinski &Veber rules, molecular docking and molecular dynamics simulation. It is understood that the mechanism of action to inhibit the activity of SHP-2 protein by compounds is mainly protein amino acid residues PHE-113, GLU-250, LEU-254, GLN-257, PRO-491, and GLN-495 bind to ligands to produce stable conformation. Finally, a series of in vitro preliminary evaluation experiments were conducted to verify the primary activity of the lead compounds. It provides a meaningful reference for the future study of SHP-2 inhibitors with better efficacy, safety, drug-like, bioavailability and drug resistance.
期刊介绍：
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;
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