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Novel Lead Structures for p38 MAP Kinase via FieldScreen Virtual Screening
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Section: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 ≥20% inhibition of p38 at 10 μM. We chose to prepare analogues of two distinct chemical series resulting in a potential lead compound with pIC50 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.
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This article has been cited by 4 ACS Journal articles (4 most recent appear below).
Molecular Dynamics Simulation and Free Energy Calculation Studies of the Binding Mechanism of Allosteric Inhibitors with p38α MAP Kinase
Ying Yang, Yulin Shen, Huanxiang Liu, and Xiaojun YaoJournal of Chemical Information and Modeling2011 51 (12), 3235-3246Molecular Dynamics Simulation and Free Energy Calculation Studies of the Binding Mechanism of Allosteric Inhibitors with p38α MAP Kinase
Ying Yang, Yulin Shen, Huanxiang Liu, and Xiaojun YaoJournal of Chemical Information and Modeling2011 51 (12), 3235-3246p38 MAP kinase is a promising target for anti-inflammatory treatment. The classical kinase inhibitors imatinib and sorafenib as well as BI-1 and BIRB-796 were reported to bind in the DFG-out form of human p38α, known as type II or allosteric kinase ...
Selectivity of Kinase Inhibitor Fragments
Paul Bamborough, Murray J. Brown, John A. Christopher, Chun-wa Chung, and Geoff W. MellorJournal of Medicinal Chemistry2011 Article ASAPSelectivity of Kinase Inhibitor Fragments
Paul Bamborough, Murray J. Brown, John A. Christopher, Chun-wa Chung, and Geoff W. MellorJournal of Medicinal Chemistry2011 Article ASAPA kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first ...
Discovery of Pyridazinopyridinones as Potent and Selective p38 Mitogen-Activated Protein Kinase Inhibitors
Bin Wu, Hui-Ling Wang, Liping Pettus, Ryan P. Wurz, Elizabeth M. Doherty, Bradley Henkle, Helen J. McBride, Christiaan J. M. Saris, Lu Min Wong, Matthew H. Plant, Lisa Sherman, Matthew R. Lee, Faye Hsieh and Andrew S. TaskerJournal of Medicinal Chemistry2010 53 (17), 6398-6411Discovery of Pyridazinopyridinones as Potent and Selective p38 Mitogen-Activated Protein Kinase Inhibitors
Bin Wu, Hui-Ling Wang, Liping Pettus, Ryan P. Wurz, Elizabeth M. Doherty, Bradley Henkle, Helen J. McBride, Christiaan J. M. Saris, Lu Min Wong, Matthew H. Plant, Lisa Sherman, Matthew R. Lee, Faye Hsieh and Andrew S. TaskerJournal of Medicinal Chemistry2010 53 (17), 6398-6411The p38 mitogen-activated protein kinase (MAPK) plays an important role in the production of proinflammatory cytokines, making it an attractive target for the treatment of various inflammatory diseases. A series of pyridazinopyridinone compounds were ...
One-Pot Synthesis of 4,6-Diaryl-2-oxo(imino)-1,2-dihydropyridine-3-carbonitrile; a New Scaffold for p38α MAP Kinase Inhibition
Aya M. Serry, Sabine Luik, Stefan Laufer and Ashraf H. AbadiJournal of Combinatorial Chemistry2010 12 (4), 559-565One-Pot Synthesis of 4,6-Diaryl-2-oxo(imino)-1,2-dihydropyridine-3-carbonitrile; a New Scaffold for p38α MAP Kinase Inhibition
Aya M. Serry, Sabine Luik, Stefan Laufer and Ashraf H. AbadiJournal of Combinatorial Chemistry2010 12 (4), 559-565Two series of new compounds with the general formula 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles and their isosteric 2-imino derivatives were synthesized by the multicomponent reaction of the appropriate acetophenone, aromatic aldehyde, ammonium ...
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- Published In Issue July 23, 2009
- Article ASAPJune 02, 2009
- Received: November 06, 2008
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