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QSAR analysis of 3-pyrimidin-4-yl-oxazolidin-2-one derivatives isocitrate dehydrogenase inhibitors using Topomer CoMFA and HQSAR methods

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Abstract

A series of mIDH1 inhibitors derived from 3-pyrimidine-4-oxazolidin-2-ketone derivatives were studied by QSAR model to explore the key factors that inhibit mIDH1 activity. The generated model was cross-verified and non-cross-verified by Topomer CoMFA and HQSAR methods; the independent test set was verified by PLS method; the Topomer search technology was used for virtual screening and molecular design; and the Surflex-Dock method and ADMET technology were used for molecular docking, pharmacology and toxicity prediction of the designed drug molecules. The Topomer CoMFA and HQSAR cross-validation coefficients q2 are 0.783 and 0.784, respectively, and the non-cross-validation coefficients r2 are 0.978 and 0.934, respectively. Ten new drug molecules have been designed using Topomer search technology. The results of molecular docking and ADMET show that the newly designed drug molecules are effective. The docking situation, pharmacology and toxicity prediction results are good. The model can be used to predict the bioactivity of the same type of new compounds and their derivatives. The prediction results of molecular design, molecular docking and ADMET can provide some ideas for the design and development of novel mIDH1 inhibitor anticancer drugs, and provide certain theoretical basis of the experimental verification of new compounds in the future.

Graphic abstract

Newly designed molecules after docking with corresponding proteins in the PDB library, it can explore the targets of drug molecules acting with large proteins and the related force, which is very helpful for the design of new drugs and the mechanism of drug action.

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Funding

This project was funded by the National Natural Science Foundation of China (21475081), the Natural Science Foundation of Shaanxi Province (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, Shuai Bian, Xing Zhang & Ding Luo

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

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

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  1. Jian-Bo Tong
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  2. Shuai Bian
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  3. Xing Zhang
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  4. Ding Luo
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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, Shuai Bian, Xing Zhang, and Ding Luo. Data analysis was performed by Jian-Bo Tong. The first draft of the manuscript was written by Shuai Bian 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., Bian, S., Zhang, X. et al. QSAR analysis of 3-pyrimidin-4-yl-oxazolidin-2-one derivatives isocitrate dehydrogenase inhibitors using Topomer CoMFA and HQSAR methods. Mol Divers 26, 1017–1037 (2022). https://doi.org/10.1007/s11030-021-10222-6

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