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[…] atching reference ligands to the pharmacophore as well as docking them into a H3 structure model. The additional pharmacophore element represents a cationic ligand functionality that interacts with a Glu residue in position 5.46 × 461. This residue has been shown by mutagenesis studies be important for binding of imidazole- and pyridine-containing ligands, including histamine, ., Histamine H3 receptor reference ligands were downloaded from ChEMBL and the IUPHAR guide to pharmacology databases. We used only the ligands with submicromolar dose-response affinity or activity values (K i, pK i, EC50, pEC50, IC50 and pIC50), and the highest assay confidence scores: 8 or 9. The screening database, eMolecules plus, was prepared with LigPrep to desalt, add hydrogen atoms and generate tautomers, stereoisomers (max 32) and 3D conformations (max 10 ring conformations). Epik and the OPLS 2005 force field were applied to generate charge states at pH: 7.0 ± 1.0. LigFilter was used to remove structures with reactive functional groups and match the properties (Supplementary Table ) of the reference ligands., The Phase database, containing both reference ligands and screening compounds, was prepared with 100 maximum conformers, up to 10 conformations per rotatable bond, thorough conformational sampling, conformational variation of amide bonds and a maximum relative energy difference of 6.0 kcal/mol. A minimum of four matching pharmacophore elements was required and a preference was set for partial matches involving more sites. Hits were sorted by fitness score a […]

Pipeline specifications

Software tools eMolecules, LigPrep, Epik
Databases IUPHAR
Organisms Homo sapiens