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Phenylalkylamines in calcium channels: computational analysis of experimental structures

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Abstract

Experimental 3D structures of calcium channels with phenylalkylamines (PAAs) provide basis for further analysis of atomic mechanisms of these important cardiovascular drugs. In the crystal structure of the engineered calcium channel CavAb with Br-verapamil and in the cryo-EM structure of the Cav1.1 channel with verapamil, the ligands bind in the inner pore. However, there are significant differences between these structures. In the crystal structure the ligand ammonium group is much closer to the ion in the selectivity-filter region Site 3, which is most proximal to the inner pore, than in the cryo-EM structure. Here we used Monte Carlo energy minimizations to dock PAAs in calcium channels. Our computations suggest that in the crystal structure Site 3 is occupied by a water molecule rather than by a calcium ion. Analysis of the published electron density map does not rule out this possibility. In the cryo-EM structures the ammonium group of verapamil is shifted from the calcium ion in Site 3 either along the pore axis, towards the cytoplasm or away from the axis. Our unbiased docking reproduced these binding modes. However, in the cryo-EM structures detergent and lipid molecules interact with verapamil. When we removed these molecules, the nitrile group of verapamil bound to the calcium ion in Site 3. Models of Cav1.2 with different PAAs suggest similar binding modes and direct contacts of the ligands electronegative atoms with the calcium ion in Site 3. Such interactions explain paradoxes in structure–activity relationships of PAAs.

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Abbreviations

BrVp:

Br-verapamil

MC:

Monte Carlo

MCM:

MC-minimizations

PAA:

Phenylalkylamine

RMS:

Root Mean Square

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Acknowledgements

This work was supported by grants to BSZ from the Natural Sciences and Engineering Research Council of Canada (GRPIN-2014–04894) and Russian Foundation for Basic Research (17–04-00549-П). ZY acknowledges support from the National Key Research and Development Program of China (2017YFD0201400, 2017YFD0201403). Computations were performed using facilities provided by Compute Canada (www.computecanada.ca).

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Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russian Federation

    Denis B. Tikhonov & Boris S. Zhorov

  2. Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China

    Lianyun Lin & Zhiguang Yuchi

  3. Almazov National Medical Research Centre, St. Petersburg, Russia, 197341

    Daniel S. C. Yang & Boris S. Zhorov

  4. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada

    Boris S. Zhorov

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  1. Denis B. Tikhonov
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  4. Zhiguang Yuchi
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  5. Boris S. Zhorov
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Correspondence to Denis B. Tikhonov, Zhiguang Yuchi or Boris S. Zhorov.

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Tikhonov, D.B., Lin, L., Yang, D.S.C. et al. Phenylalkylamines in calcium channels: computational analysis of experimental structures. J Comput Aided Mol Des 34, 1157–1169 (2020). https://doi.org/10.1007/s10822-020-00330-0

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