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

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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, \( {r}_{\mathrm{pred}}^2 \) = 0.817; HQSAR with q2 = 0.767, r2 = 0.959, \( {r}_{\mathrm{pred}}^2 \) = 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.

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All data generated or analyzed during this study are included in the article and supplementary materials.

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Funding

This work was supported by the National Natural Science Funds of China (21475081), the Natural Science Foundation of Shaanxi Province of China (2019JM-237), and the Graduate Innovation Fund of Shaanxi University of Science and Technology.

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Authors and Affiliations

  1. College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi’an, 710021, China

    Jian-Bo Tong, Ding Luo, Xing Zhang & Shuai Bian

  2. Shaanxi Key Laboratory of Chemical Additives for Industry, Xi’an, 710021, China

    Jian-Bo Tong, Ding Luo, Xing Zhang & Shuai Bian

Authors
  1. Jian-Bo Tong
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  2. Ding Luo
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  3. Xing Zhang
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  4. Shuai Bian
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Contributions

All authors contributed to the study conception and design. Material preparation and data collection were performed by Jian-Bo Tong, Ding Luo, Xing Zhang, and Shuai Bian. Data analysis was performed by Jian-Bo Tong. The first draft of the manuscript was written by Ding Luo and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jian-Bo Tong.

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Tong, JB., Luo, D., Zhang, X. et al. Design of novel SHP2 inhibitors using Topomer CoMFA, HQSAR analysis, and molecular docking. Struct Chem 32, 1061–1076 (2021). https://doi.org/10.1007/s11224-020-01677-8

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  • DOI: https://doi.org/10.1007/s11224-020-01677-8

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