REVIEWS Targeted molecular diversity in drug discovery: integration of structure-based design and combinatorial chemistry Jin Li, Christopher W. Murray, Bohdan Waszkowycz and Stephen C. Young A powerful new approach emerging in drug discovery research combines computational screening of virtual combinatorial libraries against a therapeutic target and targeted combinatorial library synthesis. This new approach includes positive features from both structure- based design and combinatorial chemistry. It has the potential of producing combinatorial libraries with a high hit rate, and hence accelerates the generation of quality lead compounds. The effectiveness of this novel approach has been shown by the design and synthesis of potent inhibitors for serine and aspartyl proteases. A n important step in drug discovery is the cost- effective identification of lead molecules. In recent years, combinatorial clnemical synthesis methods have been developed :0 the stage where large libraries of compounds can be synthesized and tested w-ith moderate cost and effort 1-3. In particular, very large libraries of peptides and peptoids have been synthesized, leading to the identification of novel, active compounds4-L As peptide-like molecules often display unsuitable pharmaco- kinetics for oral dosing, there is considerable interest in extending combinatorial libraries to a wider range of pep- toid structures and especially to small[ organic molecules ~-1°. A combinatorial library of small organic molecules typi- cally consists of a common central template or scaffold onto which different sets of substituents are attached at several substituent positions (Figure 1). The substituents will be derived from available chemical reagents, and the template is either an available reagent, or is easily synthesized, or is formed in the synthesis of library members. Large libraries are necessary in random screening applications because a wide diversity of chemical compounds is needed to ensure that there is an adequate number of high-quality hits. In many cases, the synthesis of full libraries may be problema- tic because of the enormous numbers of library members. Diversity analysis of the substituents is used to reduce the library to a more manageable size 11q4. Figure 2 illustrates the basic concepts underlying diversity analysis. Chemical compounds can be classified according to the values of calculated molecular properties (descrip- tors), such as chemical functionality, shape, physicochemi- cal properties and the pharmacophores a molecule can matchlL Molecules with similar values of relevant molecular descriptors are likely to have similar biological activities. In Jin Li*, Christopher W. Murray, Bohdan Waszkowycz and Stephen C. Young, Proteus Molecular Design Ltd, Beechfield House, Lyme Green Business Park, Macclesfield, Cheshire, UK SK11 0JL. *tel: +44 1625 500555, fax: +44 1625 500666, e-mail: jin@proteus.co.uk DDT Vol. 3, No. 3 March 1 9 9 8 Copyright © F_lsevier Science Ltd.Arl rightsreserved. 1359-6446/98/$19.00. Pit: S1359-6446(97)01138-0 105