title: Sequential application of ligand and structure based modeling approaches to index chemicals for their hH4R antagonism.
abstract: The human histamine H4 receptor (hH4R), a member of the G-protein coupled receptors (GPCR) family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH4R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH4R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE) and Iterative Stochastic Elimination (ISE) approach, were used to index chemicals for their hH4R bioactivity. An application of the prediction model on external test set composed of more than 160 hH4R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ∼ 4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH4R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH4R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and increase the enrichment factors in a synergistic manner.
authors.affiliation: Department of Chemical Sciences, University of Catania, Catania, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pappalardo
authors.affiliation: Drug Discovery Informatics Lab, QRC-Qasemi Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Shachaf
authors.affiliation: Etnalead s.r.l., Scuola Superiore di Catania, University of Catania, Catania, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Basile
authors.affiliation: National Research Council, Institute of Biostructures and Bioimaging, Catania, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Milardi
authors.affiliation: Drug Discovery Informatics Lab, QRC-Qasemi Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel.
authors.forename: Mouhammed
authors.initials: M
authors.lastname: Zeidan
authors.affiliation: Drug Discovery Informatics Lab, QRC-Qasemi Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel.
authors.forename: Jamal
authors.initials: J
authors.lastname: Raiyn
authors.affiliation: Etnalead s.r.l., Scuola Superiore di Catania, University of Catania, Catania, Italy; Department of Pharmaceutical Sciences, University of Catania, Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
authors.affiliation: Drug Discovery Informatics Lab, QRC-Qasemi Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel.
authors.forename: Anwar
authors.initials: A
authors.lastname: Rayan
mesh_terms: D062313:Databases, Pharmaceutical; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D048088:Informatics / Q000379:methods*; D020128:Inhibitory Concentration 50; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011968:Receptors, Histamine / Q000737:chemistry / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics; D013997:Time Factors
chemical_list: C418607:HRH4 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4