Although
the salt bridge is the strongest among all known noncovalent
molecular interactions, no comprehensive studies have been conducted
to date to examine its role and significance in drug design. Thus,
a systematic study of the salt bridge in biological systems is reported
herein, with a broad analysis of publicly available data from Protein
Data Bank, DrugBank, ChEMBL, and GPCRdb. The results revealed the
distance and angular preferences as well as privileged molecular motifs
of salt bridges in ligand–receptor complexes, which could be
used to design the strongest interactions. Moreover, using quantum
chemical calculations at the MP2 level, the energetic, directionality,
and spatial variabilities of salt bridges were investigated using
simple model systems mimicking salt bridges in a biological environment.
Additionally, natural orbitals for chemical valence (NOCV) combined
with the extended-transition-state (ETS) bond-energy decomposition
method (ETS–NOCV) were analyzed and indicated a strong covalent
contribution to the salt bridge interaction. The present results could
be useful for implementation in rational drug design protocols.
Trazodone, a well-known antidepressant drug widely used throughout the world, works as a 5-hydroxytryptamine (5-HT2) and α1-adrenergic receptor antagonist and a serotonin reuptake inhibitor. Our research aimed to develop a new method for the synthesis of trazodone and its derivatives. In the known methods of the synthesis of trazodone and its derivatives, organic and toxic solvents are used, and the synthesis time varies from several to several dozen hours. Our research shows that trazodone and its derivatives can be successfully obtained in the presence of potassium carbonate as a reaction medium in the microwave field in a few minutes. As a result of the research work, 17 derivatives of trazodone were obtained, including compounds that exhibit the characteristics of 5-HT1A receptor ligands. Molecular modeling studies were performed to understand the differences in the activity toward 5-HT1A and 5-HT2A receptors between ligand 10a (2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one) (5-HT1A Ki = 16 nM) and trazodone. The docking results indicate the lack of the binding of ligand 10a to 5-HT2AR, which is consistent with the in vitro studies. On the other hand, the docking results for the 5-HT1A receptor indicate two possible binding modes. Crystallographic studies support the hypothesis of an extended conformation.
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