Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Identification of New Inverse Agonists of Human Histamine H₁Receptor

Abstract

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.

Molecular modelling study on human histamine H1 receptor and its applications in virtual lead identification for designing novel inverse agonists

“…Previous studies have also reported similar pharmacophore models for HHR1 antagonists [53]. As reported earlier, the distance between the PI function (generally the basic nitrogen atom) and the aromatic part of the ligand ought to be around 6 Å [32,54]. In our model, it is 6.267 Å between PI and RA, and 6.361 Å between PI and HP features, respectively.…”

“…BLAST (blastp) search [43] as implemented in DS against Protein Data Bank (PDB) was employed to search for the proteins that are crystallographically determined and closely related to HHR1. As an update to our previous study, where squid rhodopsin was used as a template to build homology models [32], recently determined GPCR proteins, namely adenosine A2A receptor (A2AR) [44] and b2 adrenergic receptor (B2AR) [45] of human were used as possible templates from the BLAST search to build two different homology models of HHR1. The Align Multiple Sequences protocol of DS was utilised to align the template and the target sequences.…”

“…Compounds predicted for their inverse agonist activity using the same assay protocol were employed in pharmacophore generation [30]. A total of 43 compounds with experimental inverse agonistic properties were used in this study [30,31]; this set of compounds is an updated set of our previous set [32]. The 18 compounds with a greater diversity in terms of their chemical structures and activity values were used as the training set and rest of the compounds were utilised, as the test set, in validation of the generated pharmacophore models.…”

3D-QSAR based pharmacophore modeling and virtual screening for identification of novel pteridine reductase inhibitors

“…This further necessitates exploration of the binding preferences of the known inhibitors in the context of structure activity relationship and the identification of potential novel lead molecules against PTR1. Pharmacophore modeling is one of the best 3D-QSAR methods which have been successfully applied to drug discovery process [19,20]. In the present study, based on the knowledge of the L. major inhibitors of PTR1 in the literature and the co-crystal structures of the complexes of the same; pharmacophore modeling, docking, and 3D QSAR studies have been performed.…”

Synthesis and structure–activity relationship of tricyclic carboxylic acids as novel anti-histamines

“…Similar results were reported with Olopatadine-related compounds, that is, dibenzoxepin-7-carboxylic acid compounds showed weaker H 1 binding affinity than dibenzooxepin-3-carboxylic acid compounds. 20 Thangapandian et al have reported that the lipophilic cavity in H 1 receptor take part in antagonist binding, 21 and Ram et al have reported that phenyl or indole rings interact with electron rich group in H 1 receptor. 22 Therefore, it is believed that the position of the oxygen atom in dibenzooxazepins can affect lipophilic interaction.…”