Library lead-finding

Diverse libraries can be used for lead finding by screening against several different targets. The selected compounds should cover the biological activity space well. 

Grassy, G., Yasri, A., Sans, P., Armbruster, A. M., Lahana, R. and Fauchere, J. L. (1997) Molecular dynamics simulations as a tool to investigate the three-dimensional diversity of peptide and pseudopeptide libraries. In Computer-assisted lead finding and optimization. Current tools for medicinal chemistry, Van de Waterbeemd, H., Testa, B., and Folkers, G. (eds.), Wiley-VCH, Basel, pp. 209-222. 

III. Lead Discovery Designing a Library for Finding New Leads.224... 

III. LEAD DISCOVERY DESIGNING A LIBRARY FOR FINDING NEW LEADS... 

Without the constraints imposed by pre-existing lead structures, identified from the conventional compound sources, like corporate collections or natural extracts, the design of combinatorial libraries for lead finding (discovery libraries) may concentrate on the generation of highly diverse molecules with... 

A partial list of companies that sell natural products can be found at http //www.rechemical. com/natural-compounds. Several such companies have entered agreements with the same large pharmaceutical companies that were so eager to abandon in-house natural product groups. Such deals usually involve the supply of natural product samples or the provision of certain screens and targets as identified by the large companies against their natural products libraries to find new and novel natural product leads (Bouley, 2007 Rouhi, 2003). 

Lundstedt, T., Andersson, P.M., Clementi, S., Cruciani, G., Kettaneh, N., Linusson, A., Norden, B., Pastor, M., Sjostrom, M. and Wold, S. Intelligent Combinatorial Libraries. In Computer-Assisted Lead Finding and Optimization Ed. H. van de Waterbeemd, Verlag Helvetica Chimica Acta. Basel, Switzerland, 1997, 191-208. 

Noteworthy in this perspective is the work by Bemis and Murcko, who developed a method for decomposing molecules into frameworks, sidechains, and linkers and analyzed the statistical occurrence of the frameworks within a subset of drugs listed in the CMC catalog [112]. This analysis revealed that only 32 frameworks describe the shapes of half the drugs in the CMC set (-5000 compounds) and resulted in the design of the SHAPES NMR screening library-a limited but diverse library of small molecules derived from the shapes most commonly found - which Vertex uses within the lead-finding process [113]. 

Ion channels are of potential interest in several therapeutic areas. However, appropriate high-throughput assays to test several hundred thousand compounds against a particular ion channel still lack sufficient signal-to-noise ratios [57]. Therefore, a biased ion channel library is of high interest for lead finding. 

To speed up the lead-finding process, the design of specialized libraries that comply with many different requirements has become increasingly important ... 

Library for repository expansion and high-through-put screening (HTS) (lead finding) Maximum diversity of single library. Maximum diversity within a set of libraries. Find gaps in the represented chemical space. 

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