Multimethod approach to understanding the different affinity for the 5-HT1A receptor of three regioisomers of novel arylpiperazine salicylamide ligand
Authors:
- Edyta Pindelska,
- Mateusz A. Mogilnicki,
- Jolanta Jaśkowska,
- Izabela D. Madura
Abstract
Three isomers of an arylpiperazine derivative with different positioning of the amide group to the labile alkyl chain, showing varied affinity to the serotonin 5-HT1A receptor, are discussed. Using experimental studies (X-ray, NMR, and ssNMR), quantum chemical calculations (for gaseous and solid phases), and modern cheminformatics methods, the molecular and crystal structures of three regioisomers (ortho, meta, and para) were meticulously analyzed. The results showed that for the best activity, the proper positioning of the hydrogen bond active group is essential, the energy of the H-bonds, and the propensity to aromatic interactions. Crystal data, although the best tool for obtaining knowledge about the spatial distribution of active molecular fragments, most often refers to one point in space determined by the number of degrees of freedom of the molecule. In order to recognize other conformations, e.g., when performing simulations of receptor-ligand complexes, it is worth applying modern knowledge-based methods using big data (in this case, crystallographic databases). In the discussed case, the conformation of the ortho isomer found in the crystal and in the previously performed docking studies differs in terms of the amide group orientation. We were curious if we could explain this observation by analyzing the molecular and crystal structures in detail. Our studies have shown that the ortho isomer conformation in the crystal might not be optimal, and the observed intramolecular hydrogen bond with an estimated energy of approximately 30 kJ/mol, poorly represented in the entire Cambridge Structural Database, can be easily broken in a protein environment. In the crystal, this isomer forms the weakest intermolecular interactions. In comparison, the least active para isomer molecule is too prolate and creates the strongest intermolecular H-bonds between amide fragments, although the geometry of these interactions is statistically unusual. On the other hand, the meta isomer, the best of the ligands, shows medium asphericity and creates the most effective intermolecular interactions in the crystal and in the modeled ligand-receptor complex.
- Record ID
- CUT9830d0393b46403c9ab72213ec9b7876
- Publication categories
- ;
- Author
- Journal series
- Crystal Growth & Design, ISSN 1528-7483, e-ISSN 1528-7505
- Issue year
- 2023
- Vol
- 23
- No
- 8
- Pages
- 5827-5838
- Other elements of collation
- rys.; schem.; tab.; wykr.; Bibliografia (na s.) - 5836-5838; Bibliografia (liczba pozycji) - 53; Oznaczenie streszczenia - Abstr.; Numeracja w czasopiśmie - Vol. 23, Iss. 8
- Substantive notes
- The Supporting Informationis available at https://pubs.acs.org/doi/10.1021/acs.cgd.3c00438
- Keywords in English
- crystals, molecular interactions, molecular structure, 5-HT1A receptor ligand, regioisomers, arylpiperazine, salicylamide, molecules, noncovalent interactions
- ASJC Classification
- ; ;
- DOI
- DOI:10.1021/acs.cgd.3c00438 Opening in a new tab
- URL
- https://pubs.acs.org/doi/10.1021/acs.cgd.3c00438 Opening in a new tab
- Language
- eng (en) English
- License
- Score (nominal)
- 100
- Score source
- journalList
- Score
- Publication indicators
- Additional fields
- Indeksowana w: Web of Science, Scopus
- Uniform Resource Identifier
- https://cris.pk.edu.pl/info/article/CUT9830d0393b46403c9ab72213ec9b7876/
- URN
urn:pkr-prod:CUT9830d0393b46403c9ab72213ec9b7876
* presented citation count is obtained through Internet information analysis, and it is close to the number calculated by the Publish or PerishOpening in a new tab system.