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Flat or angular? The impact of the nitrogen atom hybridization on the docking results for arylpiperazine derivatives as an example

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Abstract

Structure-based virtual screening has become a standard approach in modern drug discovery. It involves molecular docking and estimation of the ligand binding likelihood based on the scoring function. Surprisingly, in the search for new pharmaceuticals, one of the bottlenecks can be the ligand’s 3D structure prediction, especially for molecules with amine groups. In our work, the impact of the nitrogen atom hybridization in arylpiperazine derivatives on the results of docking to serotonin receptor type 7 is discussed. Our docking/re-docking studies show that the nitrogen lone pair may be involved in weak ligand–protein interactions. The presented results suggest that assumption of amine group planarity in the arylpiperazine 3D structure prediction may be a misleading factor in computer-aided drug discovery, influencing active conformation prediction. With our paper, we would like to raise awareness that in the case of compounds with amine groups, special care must be taken in the 3D ligand’s structure preparation for molecular docking studies.

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Acknowledgments

Quantum mechanics calculations and docking calculations using AutoDock4 were performed using PL-Grid Infrastructure and resources provided by ACC Cyfronet AGH (Cracow, Poland).

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Authors and Affiliations

  1. Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Kraków, Poland

    Katarzyna Rzęsikowska, Mateusz Jabłoński & Justyna Kalinowska-Tłuścik

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  1. Katarzyna Rzęsikowska
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  2. Mateusz Jabłoński
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  3. Justyna Kalinowska-Tłuścik
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Correspondence to Justyna Kalinowska-Tłuścik.

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Rzęsikowska, K., Jabłoński, M. & Kalinowska-Tłuścik, J. Flat or angular? The impact of the nitrogen atom hybridization on the docking results for arylpiperazine derivatives as an example. Struct Chem 31, 823–829 (2020). https://doi.org/10.1007/s11224-019-01469-9

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