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John Irwin is an Adjunct Assistant Professor in the Department of Pharmaceutical Chemistry at the University of California San Francisco. He works together with Brian Shoichet on methods to discover new chemistry for biological targets using 2D (ligand-based) and 3D (docking) methods. He applies these methods to various projects, and participates in numerous collaborations.
He develops the ZINC database of commercially available compounds for virtual screening and the DUD database for benchmarking virtual screening methods. His most recent product is DOCK Blaster, a free virtual screening service that aims to make docking as reliable and easy to use - if not nearly as fast - as BLAST.
He received his Ph.D. for work with Jack Dunitz in chemical crystallography in 1991 at ETH Zurich. He worked at a startup molecular modeling company before joining Gerard Bricogne's group at the Medical Research Council's Laboratory of Molecular Biology in Cambridge UK, developing software for new macromolecular crystallographic structure solution and refinement methods (BUSTER and SHARP). He spent a year and a half as a staff scientist at EMBL-EBI also in Cambridge working on the PDB cleanup project before moving to Northwestern University Medical School with Brian Shoichet in 2000 where he began work on DOCK, ZINC, and SEA.
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Retrospective and Prospective Investigation of Docking Performance
John J. Irwin, Department of Pharmaceutical Chemistry, University of California San Francisco, Byers Hall, 1700 4th St, Mailbox 2550, San Francisco CA 94158-2330, USA
Virtual screening is the most practical method to leverage structure for ligand discovery, and as a consequence is widely used by both pharma and academic groups. Unfortunately, the technique retains important weaknesses, and continues to be challenging to use effectively, even by experts. In principle, one would like to evaluate docking by its ability to predict ligand binding affinities, but this is now beyond the field. In practice, docking is judged by separation of likely ligands from the vast majority of database molecules (decoys) that are unlikely to bind, typically in retrospective calculations. For such enrichment factors to be meaningful, the ligands and decoys must be property matched, so that enrichment is not simply due to trivial separation by physical properties such as molecular weight or hydrophobicity. We have addressed this problem by creating a directory of universal decoys (DUD), containing 2950 ligands and 95,316 property-matched decoys for 40 targets. Another way to evaluate docking is to compare it to high throughput screening (HTS). We prospectively docked 70,563 compounds against AmpC beta lactamase, and compared our prediction with HTS followed by careful secondary assays. Surprisingly, although there were 1274 “hits”, HTS failed to identify a single non-covalent inhibitor at 30 uM. Reviewing the top scoring docked ligands, we selected 16 compounds to test in the lab at higher concentration. We found two compounds, the better of which had a Ki of 37 uM, and could be progressed through routine medicinal chemistry to a Ki of 8 uM.
References
1. Babaoglu, B, Simeonov, A, Irwin JJ, Nelson ME, Feng B, Thomas CJ, Cancian L, Costi MP, Maltby DA, Jadhav A, Inglese J, Austin CP and Shoichet BK, A comprehensive mechanistic analysis of hits from high throughput and docking screens against beta lactamase, J. Med. Chem. (2008), in press.
2. Huang N, Shoichet BK*, Irwin JJ*, Benchmarking sets for Molecular Docking, J. Med. Chem., 49(23), 6789-6801 (2006).
3. Irwin JJ, Community benchmarks for virtual screening, J. Comput. Aided Mo.l Des. (2008), available online.
4. DUD is available free at http://dud.docking.org/.
5. ZINC is available free at http://zinc.docking.org/.
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