Docking can be used to discover novel ligands. We illustrate some of the advantages of docking, while listing some problem areas, in several projects undertaken by the Shoichet lab, using very similar technology to that used by Blue Dolphin. There are other cases using other docking techniques undertaken by other labs, both in industry and in academia, in the literature. For example, we think highly of many of the docking papers by Leslie Kuhn, Art Olson, Ruben Abagyan, Michel Vieth and Martin Stahl. We focus on these ones below because we know them best, and we can reveal the gory details because they are entirely public. We use each story to illustrate the various ways in which discovery projects proceed.

Target:Protein tyrosine phosphatase 1B (PTP-1B), a target for type II diabetes. This case study illustrates a best-case scenario for docking.

Database:400,000 compounds screened via HTS compared to 250,000 commercially available compounds docked.

Reference: Doman TN, McGovern SL, Witherbee BJ, Kasten TP, Kurumbail R, Stallings WC, Connolly DT, Shoichet BK. Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. J Med Chem 45 (11), 2213-21 (2002). [Pubmed | DOI | NRDD Highlight | Faculty of 1000 | Download PDF]

Target: AmpC beta lactamase. A target for antibiotic resistance. Illustrates discovery of completely novel chemistry. Docking made a correct prediction for the right reasons.

Database: 250,000 commercially available compounds (ACD + Specs + Maybridge)

Reference: Powers RA, Morandi F, Shoichet BK. Structure-based discovery of a novel, non-covalent inhibitor of AmpC β-lactamase. Structure 10 (7), 1013-23 (2002).
[Pubmed | DOI | PDB 1L2S | Download PDF]

Targets: Model Cavity Sites
Database: ACD, 56,000 small commercially available molecules.

BQ Wei, WA Baase, L Weaver, BW Matthews* & BK Shoichet*. A Model Binding Site for Testing Scoring Functions in Molecular Docking. J. Mol. Biol. 322, 339-355 (2002)

and others...

Target:Tm0936: Substrate discovery and assignment of function from docking.

Database:Metabolites (KEGG) represented as high energy intermediates during nucleophilic attack by a hydroxide nucleophile.

Reference: JC Hermann, R Mart-Arbona, AA Fedorov, E Federov, SC Almo, BK Shoichet, FM Raushel. Structure-based activity prediction for an enzyme of unknown function. Nature, Aug 16 (2007).

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