Expanding the range of “druggable” targets with natural product-based libraries: An academic perspective

Tri-Institutional Training Program in Chemical Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 422, New York, NY 10065, USA.
Current opinion in chemical biology (Impact Factor: 6.81). 03/2010; 14(3):308-14. DOI: 10.1016/j.cbpa.2010.02.001
Source: PubMed


Existing drugs address a relatively narrow range of biological targets. As a result, libraries of drug-like molecules have proven ineffective against a variety of challenging targets, such as protein-protein interactions, nucleic acid complexes, and antibacterial modalities. In contrast, natural products are known to be effective at modulating such targets, and new libraries are being developed based on underrepresented scaffolds and regions of chemical space associated with natural products. This has led to several recent successes in identifying new chemical probes that address these challenging targets.

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    • "Although they may contain several millions of compounds , they still explore only a minute fraction of the chemical space, because this one is estimated to be in the range of 10 18 –10 200 molecules (Dobson, 2004). Because assembling and maintaining a screening collection is expensive and because the chance of obtaining valuable hits is generally linked to the quality of the compounds, tremendous efforts have been spent in pharmaceutical companies and in academic laboratories to develop protocols facilitating the design of ''better and safer'' libraries while reducing the threat of missing possible active series (Baell, 2010; Bauer et al., 2010; Charifson and Walters, 2002; Davies et al., 2006; Drewry and Macarró n, 2010; Gleeson et al., 2011b; Hert et al., 2009; Hu et al., 2011; Macarró n and Luengo, 2011; Orry et al., 2006; Park et al., 2011; Pitt et al., 2009; Renner et al., 2011; Sperandio et al., 2010b; Stocks et al., 2009). Many chemical databases and compound collections are freely available online (Ekins and Williams, 2010; Ertl and Jelfs, 2007; Gozalbes and Pineda-Lucena, 2011; Richard et al., 2006; Villoutreix et al., 2007). "
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    • "It has been argued that libraries of natural products and their derivatives are actually better suited for such screens simply because they span a much broader chemical space than most synthetic compound libraries currently available for this purpose [55]. It has even been proposed that screening libraries should be intentionally optimized by adding to them molecules with biogenic or natural-product-like scaffolds [56], further underlining the value of natural products to such strategies. "
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