Bioactive small molecules screening

Selman Waksman s commitment to the isolation and screening of soil bacteria in the search for bioactive small molecules, especially potential antibiotics, was validated by the discovery of streptomycin. This led to the creation of the modem biopharmaceutical industry and the subsequent isolation of tens of thousands of bioactive small molecules from soil bacteria and other environments. A proportion of these compounds have become highly successfnl therapeutics, not only for all types of infectious diseases, but also in the treatment of many other human and animal ailments and as anticancer, immnno-modnlatory, and cardiovascular agents. Waksman and Fleming could be considered the fathers of chemical biology (Figure 1.1). 

For example, see the ChEMBL database http //www.ebi.ac.uk/chembl/. This public repository of bioactive small molecules, contains 2D structures, calculated properties (e.g., logP, molecular weight, Lipinski parameters, etc.) and abstracted bioactivities (e.g., binding constants, pharmacology, and ADMET data). The data, its maintenance and support is funded by the Wellcome Trust. In the case of singletons, screen hits with no structurally related analogs, these will require further exploration by SAR-by-synthesis for appropriate assessment. 

Fig. 4. Bioactive molecules from the synthesis and screening of drug-like scaffold, small-molecule libraries.

The thrombin-inhibitor example demonstrates a path from the bioactive 3-D struc-tnre of a peptide to small molecules. However, unambiguous structural information on the bioactive ligand conformation needed for snch a transformation is only available in a limited nnmber of cases. In most cases, additional complementary information has to be nsed to deduce the bioactive conformation of a bonnd ligand, and thns a pharmacophore model for virtual screening or design. 

Burns AR, Kwok TC, Howard A, Houston E, Johanson K, Chan A, Cutler S.R, McCourt P, Roy PJ. High-throughput screening of small molecules for bioactivity and target identification in Caenorhabditis elegans. Nat. Protoc. 2006 1 1906-1914. Zlokarnik G. Eusions to beta-lactamase as a reporter for gene expression in live mammalian cells. Methods Enzymol. 2000 326 221-244. 

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