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Open AccessArticle

The Significance of Halogen Bonding in Ligand–Receptor Interactions: The Lesson Learned from Molecular Dynamic Simulations of the D4 Receptor

1
Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Cracow, Poland
2
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland
3
Faculty of Chemical Engineering and Technology, Cracow University of Technology, Warszawska 24, 31-155 Cracow, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: Gianluca Ciancaleoni
Molecules 2020, 25(1), 91; https://doi.org/10.3390/molecules25010091
Received: 5 December 2019 / Revised: 22 December 2019 / Accepted: 23 December 2019 / Published: 25 December 2019
(This article belongs to the Special Issue Halogen Bonds: Combining Experiment and Theory)
Recently, a computational approach combining a structure–activity relationship library containing pairs of halogenated ligands and their corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was developed and used to search for amino acids frequently targeted by halogen bonding, also known as XB hot spots. However, the analysis of ligand–receptor complexes with halogen bonds obtained by molecular docking provides a limited ability to study the role and significance of halogen bonding in biological systems. Thus, a set of molecular dynamics simulations for the dopamine D4 receptor, recently crystallized with the antipsychotic drug nemonapride (5WIU), and the five XSAR sets were performed to verify the identified hot spots for halogen bonding, in other words, primary (V5x40), and secondary (S5x43, S5x461 and H6x55). The simulations confirmed the key role of halogen bonding with V5x40 and H6x55 and supported S5x43 and S5x461. The results showed that steric restrictions and the topology of the molecular core have a crucial impact on the stabilization of the ligand–receptor complex by halogen bonding. View Full-Text
Keywords: halogen bond; XB hot spots; molecular dynamics; dopamine D4 receptor halogen bond; XB hot spots; molecular dynamics; dopamine D4 receptor
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Kurczab, R.; Kucwaj-Brysz, K.; Śliwa, P. The Significance of Halogen Bonding in Ligand–Receptor Interactions: The Lesson Learned from Molecular Dynamic Simulations of the D4 Receptor. Molecules 2020, 25, 91.

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