title: Novel lead structures for p38 MAP kinase via FieldScreen virtual screening.
abstract: p38 MAP kinase has received considerable interest in the pharmaceutical industry and remains a valid and interesting target for the treatment of inflammation. To discover novel p38 inhibitors, we applied the ligand-based virtual screening technique, FieldScreen, to 1.2 million commercially available compounds. Fifty-eight diverse compounds were selected for biological analysis, using molecular field similarity to known inhibitors, while explicitly removing any structure that shared a scaffold with previously reported p38 inhibitors. Of these, 11 (19%) showed >or=20% inhibition of p38 at 10 microM. We chose to prepare analogues of two distinct chemical series resulting in a potential lead compound with pIC(50) of 6.4. Modeling of SAR using FieldAlign, a ligand alignment protocol, was used to rationalize the SAR of the series of thiadiazole based inhibitors.
authors.affiliation: Cresset BioMolecular Discovery Ltd., BioPark Hertfordshire, Welwyn Garden City, Hertfordshire AL7 3AX, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Cheeseright
authors.forename: Melanie
authors.initials: M
authors.lastname: Holm
authors.forename: Frank
authors.initials: F
authors.lastname: Lehmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Luik
authors.forename: Marcia
authors.initials: M
authors.lastname: Göttert
authors.forename: James L
authors.initials: JL
authors.lastname: Melville
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D013830:Thiadiazoles; D048051:p38 Mitogen-Activated Protein Kinases