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Three-dimensional quantitative structural-activity relationship and molecular dynamics study of multivariate substituted 4-oxyquinazoline HDAC6 inhibitors

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Abstract

3D-QSAR models were established by collecting 46 multivariate-substituted 4-oxyquinazoline HDAC6 inhibitors. The relationship of molecular structure and inhibitory activity was studied by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). The results showed the models established by CoMFA (q2 = 0.590, r2 = 0.965) and CoMSIA (q2 = 0.594, r2 = 0.931) had good prediction ability. At the same time, 3D-QSAR models met the internal verification, external verification and AD test. Ten new compounds were designed based on CoMFA and CoMSIA contour maps and their pharmacokinetic/toxic properties (ADME/T) were evaluated. It was found that most compounds have well safety profile and pharmacokinetic property. Then, we explored the interaction between HDAC6 and compounds by molecular docking. The results showed that the binding mode of the new compounds with HDAC6 was the same as the template compound 46, and the hydrogen bond and hydrophobic bond played a vital role in the binding process. Molecular dynamics simulation results showed that residues Ser531, His574 and Tyr745 played key roles in the binding process. All newly designed compounds had lower energy gap and binding energy than compound 46 according to DFT analysis and free energy analysis. This study provided a theoretical reference for designing compounds of higher activity and a new idea for the development of novel HDAC6 inhibitors.

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Acknowledgements

The author would like to thank Chongqing for its financial support Entrepreneurship and Innovation Support Program for Returned Overseas Students (cx2020012), State Key Laboratory of Silkworm Genome Biology Funded by State Key Laboratory of Silkworm Genome Biology, Science and Technology Bureau of Banan District, Chongqing (sklsgb1819-2), the Scientific Research Foundation of Chongqing University of Technology, Chongqing Information Center technology and computing support university.

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  1. School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China

    Linan Zhao, Guangping Li, Yongxin Yu, Juan Wang, Haoran Liang, Mao Shu, Zhihua Lin & Yuanqiang Wang

  2. Qianjiang Central Hospital of Chongqing, Chongqing, 409099, China

    Le Fu

  3. Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, China

    Juan Wang, Haoran Liang, Mao Shu, Zhihua Lin & Yuanqiang Wang

  4. Chongqing Key Laboratory of Target Based Drug Screening and Activity Evaluation, Chongqing University of Technology, Chongqing, 400054, China

    Juan Wang, Haoran Liang, Mao Shu, Zhihua Lin & Yuanqiang Wang

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  1. Linan Zhao
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Linan Zhao involved in conceptualization and writing–original draft. Le Fu involved in software and visualization. Guangping Li involved in date curation. Yongxin Yu involved in date curation. Juan Wang involved in project administration. Haoran Liang involved in revision and research funds. Mao Shu involved in revision and editing. Zhihua Lin involved in guiding the research process. Yuanqiang Wang involved in writing–review and editing and research funding.

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Zhao, L., Fu, L., Li, G. et al. Three-dimensional quantitative structural-activity relationship and molecular dynamics study of multivariate substituted 4-oxyquinazoline HDAC6 inhibitors. Mol Divers 27, 1123–1140 (2023). https://doi.org/10.1007/s11030-022-10474-w

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