The Chemistry-Driven Drug Design and Discovery conference (San Francisco; 23–24 June 2003) (http://www. srinstitute.com/cs258) was the first in its series and was uniquely organized to integrate the applied chemistry and biology topics that currently drive drug discovery. Topics ranged from new screening techniques to structural biology to structure-guided medicinal chemistry applications. The main emphasis of the conference was on structure-based applications in drug discovery, focusing on hot areas, such as kinases and GPCRs. Fragment-based screening and assembly There is currently a need for more- frequent discovery of higher quality lead compounds to improve the productivity of R&D. Fragment-based strategies are, potentially, a powerful way to achieve this goal. Christopher Lepre (Vertex Pharmaceuticals; http://www.vpharm.com) described the ‘SHAPES’ strategy [1], which involves NMR screening of a small drug-like fragment-based library to identify initial weak hits (K D values between low μM and 5 mM) that can be followed-up by a variety of complementary methods to produce high-quality leads. Lepre outlined two successful applications of SHAPES screening for lead generation to the lipid binding protein, aP2, and the MAP kinase, JNK3, as pre-HTS and post-HTS examples, respectively. Screening only 100 compounds against aP2 by NMR methods resulted in 13 hits in the 0.3–800 μM range. X-ray structures of SHAPES hits bound to aP2, together with NMR follow-up screens, helped to generate a pharmacophore model and the development of several sub-μM leads for chemical optimization. In the JNK3 program, SHAPES NMR screening followed by a virtual screening strategy identified three scaffold classes with K i values between 0.7 and 13 μM . These three classes of compounds showed distinct binding modes by x-ray crystallography; the resulting information providing an insight that could be useful across a wide variety of kinase targets. Daniel Wyss (Schering-Plough Research Institute; http://www.schering- plough.com) described the application of ‘structure-based NMR screening approaches’ (SbN) [2] to a variety of drug discovery targets, for which HTS has failed to identify suitable leads. NMR methods were used to identify lead-like small-molecule hits from customized fragment libraries. These often initially weak hits (K d values of μM–mM) were, after some optimization, turned into viable leads through focused chemical optimization, guided by SAR and 3D structural information. Wyss discussed novel tools that use the data generated in the NMR screen to rapidly provide an accurate structural representation of protein–ligand complexes under conditions that are not favorable in traditional structural work. The application of SbN to the discovery of sub-μM competitive inhibitors against the NS3 protease of the hepatitis C virus (HCV) was discussed, as was application to the discovery of lead inhibitors of the HCV helicase in the low μM range and leads in the 20–50 nM range against the tumor biology target, human MDM2. Wyss concluded by summarizing the application of SbN as a primary screening assay to seven drug discovery programmes, together with the chemistry approaches that were used to turn the NMR-detected weak hits into viable leads. Johan Oslob (Sunesis Pharmaceuticals; http://www.sunesis.com) described the fragment assembly technique, ‘tethering’, which involves cysteine- captured ligands identified by MS from a small library of disulfide-containing molecules. Tethering enabled improved design of potent small-molecule antagonists of the IL-2/IL-2R interaction [3], the most potent analog having an IC 50 value of 60 nM, weak cell-based assay activity (EC 50 = 3 μM) and favorable PK profiles. Oslob demonstrated that a portion of the receptor-binding surface of IL-2 is highly adaptive but that tethering was still able to effectively probe ligand preferences and tolerances at this highly dynamic subsite. Dean Artis (Plexxikon; http://www. plexxikon.com) described the company’s ‘Scaffold-Based Drug Discovery™’ platform for lead generation using a highly integrated structure-guided approach that involves the screening of >20,000 selected protein family-targeted scaffold-like compounds by biochemical assays. These assays are tuned for the detection update conference DDT Vol. 8, No. 20 October 2003 1359-6446/03/$ – see front matter ©2003 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(03)02853-8 924 www.drugdiscoverytoday.com Structure-guided applications in drug discovery Daniel F. Wyss , Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA; tel: +1 908 740 3299, fax: +1 908 740 7305, e-mail: daniel.wyss@spcorp.com