Multimethod Approach to Understanding the Different Affinity for the 5-HT1A Receptor of Three Regioisomers of Novel Arylpiperazine Salicylamide Ligand

Three isomers of an arylpiperazine derivative with differentpositioningof the amide group to the labile alkyl chain, showing varied affinityto the serotonin 5-HT1A receptor, are discussed. Usingexperimental 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 thatfor the best activity, the proper positioning of the hydrogen bondactive group is essential, the energy of the H-bonds, and the propensityto aromatic interactions. Crystal data, although the best tool forobtaining knowledge about the spatial distribution of active molecularfragments, most often refers to one point in space determined by thenumber of degrees of freedom of the molecule. In order to recognizeother conformations, e.g., when performing simulations of receptor-ligandcomplexes, it is worth applying modern knowledge-based methods usingbig data (in this case, crystallographic databases). In the discussedcase, the conformation of the ortho isomer found in the crystal andin the previously performed docking studies differs in terms of theamide group orientation. We were curious if we could explain thisobservation by analyzing the molecular and crystal structures in detail.Our studies have shown that the ortho isomer conformation in the crystalmight not be optimal, and the observed intramolecular hydrogen bondwith an estimated energy of approximately 30 kJ/mol, poorly representedin the entire Cambridge Structural Database, can be easily brokenin a protein environment. In the crystal, this isomer forms the weakestintermolecular interactions. In comparison, the least active paraisomer molecule is too prolate and creates the strongest intermolecularH-bonds between amide fragments, although the geometry of these interactionsis statistically unusual. On the other hand, the meta isomer, thebest of the ligands, shows medium asphericity and creates the mosteffective intermolecular interactions in the crystal and in the modeledligand-receptor complex. Threecrystal structures of ligands for a serotonin receptorare studied. The differences in experimental affinities as well asdiscrepancies in the molecular structure in crystal and in theoreticaldocking studies are discussed. Experimental methods have been supplementedwith quantum chemical calculations and modern cheminformatics methods.

Automated summary

Three crystal structures of ligands for a serotonin receptor were studied, analyzing the differences in experimental affinities and discrepancies in the molecular structure in crystal and theoretical docking studies. Experimental methods were supplemented with quantum chemical calculations and modern cheminformatics methods.