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Computational insights into the interaction mechanism of triazolyl substituted tetrahydrobenzofuran derivatives with H+,K+-ATPase at different pH

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Abstract

The interaction mechanism of triazolyl substituted tetrahydrobenzofuran derivatives (compound 1 (N, N-Dipropyl-1-(2-phenyl-4,5,6,7-tetrahydrobenzofuran-4-yl)-1H-1,2,3-triazole-4-methanamine) and 2 (1-(2-Phenyl-4,5,6,7-tetrahydrobenzofuran-4-yl)-4-(morpholin-4-ylmethyl)-1H-1,2,3-triazole)) with H+,K+-ATPase at different pH were studied by induced-fit docking, QM/MM optimization and MM/GBSA binding free energy calculations of two forms (neutral and protonated form) of compounds. The inhibition activity of compound 1 is measured and almost unchanged at different pH, while the activity of compound 2 increases significantly with pH value decreased. This phenomenon could be explained by their protonated form percentages and the calculated binding free energies of protonated and neutral mixture of compounds at different pH. The binding free energy of protonated form is higher than that of neutral form of compound, and the protonated form could be a powerful inhibitor of H+,K+-ATPase. By the decomposed energy comparisons of residues in binding sites, Asp137 should be the key binding site to protonated form of compound because of the hydrogen bond and electrostatic interactions. These calculation results could help for further rational design of novel H+,K+-ATPase inhibitors.

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Acknowledgments

This work was supported by Natural Science Foundation of Hubei Province in China (No. 2014CFB684).

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Authors and Affiliations

  1. Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Science, China Three Gorges University, Yichang, China

    Hua-Jun Luo, Jun-Zhi Wang, Nian-Yu Huang, Wei-Qiao Deng & Kun Zou

  2. State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China

    Wei-Qiao Deng

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  1. Hua-Jun Luo
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Correspondence to Hua-Jun Luo.

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Luo, HJ., Wang, JZ., Huang, NY. et al. Computational insights into the interaction mechanism of triazolyl substituted tetrahydrobenzofuran derivatives with H+,K+-ATPase at different pH. J Comput Aided Mol Des 30, 27–37 (2016). https://doi.org/10.1007/s10822-015-9886-8

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  • DOI: https://doi.org/10.1007/s10822-015-9886-8

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