Sequential Application of Ligand and Structure Based Modeling Approaches to Index Chemicals for Their hH(4)R Antagonism (525 views)
Plosone (ISSN: 1932-6203, 1932-6203electronic, 1932-6203linking), 2014 Oct 16; 9(10): e109340-e109340.
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Paper type: Abstract, Conference, Research Support, Non-U. S. Gov'T,
Impact factor: 3.234, 5-year impact factor: 3.702
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-84908052935&partnerID=40&md5=93af7e22738d296615a56cd9de6cf2e3
Keywords: 1 (5 Chloro 2 Indolylcarbonyl) 4 Methylpiperazine, Histamine H4 Receptor, Histamine H4 Receptor Antagonist, Article, Chemoinformatics, Computer Prediction, Crystal Structure, Drug Database, High Throughput Screening, Information Science, Intelligent Learning Engine, Iterative Stochastic Elimination, Molecular Docking, Molecular Dynamics, Molecular Model,
Affiliations:
*** IBB - CNR ***
Department of Chemical Sciences, University of Catania, Catania, Italy.
Drug Discovery Informatics Lab, QRC-Qasemi Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel.
Etnalead s.r.l., Scuola Superiore di Catania, University of Catania, Catania, Italy.
National Research Council, Institute of Biostructures and Bioimaging, Catania, Italy.
Department of Pharmaceutical Sciences, University of Catania, Catania, Italy.
Etnalead s. r. l., Scuola Superiore di Catania, University of CataniaCatania, Italy
References:
Not available.
Plosone (ISSN: 1932-6203, 1932-6203electronic, 1932-6203linking), 2014 Oct 16; 9(10): e109340-e109340.
Export to BibTeX Export to EndNote
Paper type: Abstract, Conference, Research Support, Non-U. S. Gov'T,
Impact factor: 3.234, 5-year impact factor: 3.702
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-84908052935&partnerID=40&md5=93af7e22738d296615a56cd9de6cf2e3
Keywords: 1 (5 Chloro 2 Indolylcarbonyl) 4 Methylpiperazine, Histamine H4 Receptor, Histamine H4 Receptor Antagonist, Article, Chemoinformatics, Computer Prediction, Crystal Structure, Drug Database, High Throughput Screening, Information Science, Intelligent Learning Engine, Iterative Stochastic Elimination, Molecular Docking, Molecular Dynamics, Molecular Model,
Affiliations:
*** IBB - CNR ***
Department of Chemical Sciences, University of Catania, Catania, Italy.
Drug Discovery Informatics Lab, QRC-Qasemi Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel.
Etnalead s.r.l., Scuola Superiore di Catania, University of Catania, Catania, Italy.
National Research Council, Institute of Biostructures and Bioimaging, Catania, Italy.
Department of Pharmaceutical Sciences, University of Catania, Catania, Italy.
Etnalead s. r. l., Scuola Superiore di Catania, University of CataniaCatania, Italy
References:
Not available.
Sequential Application of Ligand and Structure Based Modeling Approaches to Index Chemicals for Their hH(4)R Antagonism
The human histamine H-4 receptor (hH (4) R), 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 hH (4) R 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 hH (4) R 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 hH (4) R bioactivity. An application of the prediction model on external test set composed of more than 160 hH (4) R antagonists picked from the chEMBL database gave enrichment factor of 16. 4. A virtual high throughput screening on ZINC database was carried out, picking similar to 4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH (4) R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH (4) R 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
The human histamine H-4 receptor (hH (4) R), 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 hH (4) R 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 hH (4) R 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 hH (4) R bioactivity. An application of the prediction model on external test set composed of more than 160 hH (4) R antagonists picked from the chEMBL database gave enrichment factor of 16. 4. A virtual high throughput screening on ZINC database was carried out, picking similar to 4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH (4) R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH (4) R 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
Sequential Application of Ligand and Structure Based Modeling Approaches to Index Chemicals for Their hH(4)R Antagonism
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