Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Identification of New Inverse Agonists of Human Histamine H 1 Receptor

• Published in: Bulletin of the Korean Chemical Society 2010, Vol.31 (1), p.52-58
• Main Authors: Thangapandian, Sundarapandian, Krishnamoorthy, Navaneethakrishnan, John, Shalini, Sakkiah, Sugunadevi, Lazar, Prettina, Lee, Yu-No, Lee, Keun-Woo
• Format: Article
• Language: Korean
• ISSN: 0253-2964; 1229-5949

Human histamine H1 receptor (HHR1) is a G protein-coupled receptor and a primary target for antiallergic therapy. Here, the ligand-based three-dimensional pharmacophore models were built from a set of known HHR1 inverse agonists using HypoGen module of CATALYST software. All ten generated pharmacophore models consist of five essential features: hydrogen bond acceptor, ring aromatic, positive ionizable and two hydrophobic functions. Best model had a correlation coefficient of 0.854 for training set compounds and it was validated with an external test set with a high correlation value of 0.925. Using this model Maybridge database containing 60,000 compounds was screened for potential leads. A rigorous screening for drug-like compounds unveiled RH01692 and SPB00834, two novel molecules for HHR1 with good CATALYST fit and estimated activity values. The new lead molecules were docked into the active site of constructed HHR1 homology model based on recently crystallized squid rhodopsin as template. Both the hit compounds were found to have critical interactions with Glu177, Phe432 and other important amino acids. The interpretations of this study may effectively be deployed in designing of novel HHR1 inverse agonists.