The significance of halogen bonding in ligand–receptor interactions: the lesson learned from molecular dynamic simulations of the D4 receptor
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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.
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From a synthesis point-of-view, the emergence of brorphine analogues differing in the halogen substituent seems not only feasible (only involving a one-step procedure), but may actually be likely, as halogenation is an important tool in drug optimization.
“Specifically, from a synthesis point-of-view, the emergence of brorphine analogues differing in the halogen substituent seems not only feasible (only involving a one-step procedure), but may actually be likely, as halogenation is an important tool in drug optimization (Hernandes et al., 2010; Kurczab et al., 2019; Xu et al., 2014).”
From Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization (2024) · cites this paper as Kurczab et al., 2019
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- Authors
- Kurczab, R., Kucwaj-Brysz, K., & Śliwa, P.
- Affiliations
- Maj Institute of Pharmacology (PL)
- Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Cracow, Poland
- Cracow University of Technology (PL)
- Corresponding author
- Kurczab, Rafał
- Venue
- Molecules
- Publisher
- MDPI AG
- Published
- 2019-12-25
- Volume
- 25
- Issue
- 1
- Pages
- 91
- ISSN
- 1420-3049 (ISSN-L)
- PMC
- PMC6983170
- OpenAlex
- W2998719613
- Cited by
- 31
- References
- 40
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 7 · 2023: 6 · 2022: 4 · 2021: 3 · 2020: 4
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Molecules (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Narodowe Centrum Nauki (DEC-2014/15/D/NZ7/01782)
- Topics
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Crystallography and molecular interactions
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- halogen bonding, dopamine D4 receptor, nemonapride, ligand-receptor interactions, structure-activity relationship, binding free energy, molecular dynamics simulation, antipsychotic drugs, ligand stabilization
- MeSH terms
- Halogens, Ligands, Structure-Activity Relationship, Receptors, Dopamine D4, Molecular Dynamics Simulation
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