Design of novel SHP2 inhibitors using Topomer CoMFA, HQSAR analysis, and molecular docking
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ORIGINAL RESEARCH
Design of novel SHP2 inhibitors using Topomer CoMFA, HQSAR analysis, and molecular docking Jian-Bo Tong 1,2 & Ding Luo 1,2 & Xing Zhang 1,2 & Shuai Bian 1,2 Received: 17 August 2020 / Accepted: 10 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The normal expression of SHP2 protein is a key factor in the production and action of cancer cells. Highly active SHP2 inhibitors could inhibit the promotion effect of SHP2 protein on cancer cells to effectively treating cancer. The QSAR modeling methods of 3D-QSAR (Topomer CoMFA) and HQSAR were utilized to discuss the relationship between the SHP2 inhibitory activity and the molecular structures of 35 inhibitors. A reliable and predictive model was obtained through different cutting methods and fragment combinations (Topomer CoMFA with q2 = 0.803, r2 = 0.996, r2pred = 0.817; HQSAR with q2 = 0.767, r2 = 0.959, r2pred = 0.876). Through the search of the R-group in Topomer search module and the combination of the higher activity contributing groups in the existing molecules, 18 new compounds with theoretically high anti-SHP2 activity were obtained. The docking results with SHP2 protein compared to the original ligand showed that most of the 18 new compounds could generate stable combinations in the form of hydrogen bonds. The prediction results of ADMET properties and drug-like properties indicate that they are eligible to become drugs, which is expected to become potential anti-SHP2 inhibitors and provide a certain amount of reference to foster the synthesis of SHP2 inhibitors. Keywords QSAR . SHP2 inhibitors . Topomer CoMFA . HQSAR . Molecular docking . Drug design
Introduction SHP2 is a non-receptor protein tyrosine phosphatase that plays an important role in the downstream of cell signal transduction, which is regulated by growth factors, cytokines, integrin receptors, and participates in cell survival, proliferation, and migration processes, etc. [1] SHP2 contains two Nterminal Src homology 2 (SH2) domains, protein tyrosine phosphatase (PTP) domain, and a poorly sequenced C-terminal. In its inactive state, the SHP2 protein is automatically inhibited by residues on the catalytic surface of the PTP domain and the N-SH2 domain, thereby inhibiting the activity of the SHP2 protein and restricting its active substrate from entering the catalytic site [2]. SHP2 is recruited through the
* Jian-Bo Tong [email protected] 1
College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi’an 710021, China
2
Shaanxi Key Laboratory of Chemical Additives for Industry, Xi’an 710021, China
binding of its SH2 domain to the phosphotyrosine site; the resulting conformational change exposes the catalytic site, thereby achieving precise catalytic activation of SHP2 [3]. SHP2 protein is very important in promoting the growth and survival of cancer. Activation of the RAS channel is a key factor in the normal expression of cancer cells, SHP2 is a common node that activates the RAS signal pathw
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