Structure- and ligand- based studies to gain insight into the pharmacological implications of histamine H3 receptor

• Published in: Structural chemistry 2021-06, Vol.32 (3), p.1141-1149
• Main Authors: Borota, Ana, Halip, Liliana, Curpan, Ramona, Bora, Alina, Avram, Sorin, Mracec, Maria, Mracec, Mircea
• Format: Article
• Language: English
• Subjects: Amino acids; Binding sites; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Histamine; Homology; Hydrogen bonds; Ligands; Original Research; Pharmacology; Physical Chemistry; Receptors; Theoretical and Computational Chemistry
• ISSN: 1040-0400; 1572-9001
• DOI: 10.1007/s11224-020-01711-9

In the context of unknowing the experimental structure for histamine H 3 receptor, which is a potential therapeutical target for numerous disorders and diseases, the theoretical methods can bring light and necessary information for a better understanding of the pharmacological implications of the aforementioned receptor. Thus, a homology model of human histamine H 3 receptor was built, and SiteMap was used for the identification of potential binding sites. The top-ranked site (the putative binding site) is found in a niche surrounded by TM3, TM5, TM6, and TM7 transmembranes, and it contains the following important amino acids, Asp114 (3.32) and Trp371 (6.48), which are believed to be the key residues, responsible for ligands binding and receptor activation. The docking programs (Glide and Induced Fit) were involved and by the superposition of the best poses obtained, a structure-based protein-ligand pharmacophore model with one hydrogen bond donor, one hydrogen bond acceptor, and one positive ionic feature was developed. The PHASE software, a ligand-based method, was useful in order to validate the 3D pharmacophore hypothesis, by getting a significant Quantitative Structure Activity Relationship (QSAR) model (with R 2  = 0.918 for training set and Q 2  = 0.828 for test set) for the compounds taken in the study. Further, the pharmacophore model can be used in virtual screening experiments to identify new potent ligands for histamine H 3 receptor.