Design of novel SHP2 inhibitors using Topomer CoMFA, HQSAR analysis, and molecular docking

• Published in: Structural chemistry 2021-06, Vol.32 (3), p.1061-1076
• Main Authors: Tong, Jian-Bo, Luo, Ding, Zhang, Xing, Bian, Shuai
• Format: Article
• Language: English
• Subjects: Cancer; Chemical bonds; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Hydrogen bonds; Inhibitors; Molecular docking; Molecular structure; Original Research; Physical Chemistry; Prediction models; Proteins; Theoretical and Computational Chemistry
• ISSN: 1040-0400; 1572-9001
• DOI: 10.1007/s11224-020-01677-8

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 3 D -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 q 2  = 0.803, r 2  = 0.996, r pred 2  = 0.817; HQSAR with q 2  = 0.767, r 2  = 0.959, r pred 2  = 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.