Structure-based Lead Finding

Structure-based lead finding requires a target 3D structure to start with. However, experimental elucidation of ion channel structures either NMR or X-ray crystallography is extremely difficult to achieve. Nevertheless, homology modeling of closely homologous channels to KcsA or MthK, for which 3D structures are available (see Section 8.2), makes this approach feasible. 

This study was based on a model of the outer vestibule, which was developed using indirect evidence like the structure of known ligands and data from mutational analysis. At that time, the KcsA crystal structure or other potassium channel X-ray structures were not available. Meanwhile, more detailed knowledge of the atomic details of potassium channels allows the development of homology models [47] that can be successfully used in drug design, as demonstrated by the following example. 

A recent structure-based lead-finding strategy was used for Kvl.5 inhibitors. The pore-forming domain of Kvl. 5 exhibits 54% sequence homology with the bacterial K+ channel KcsA from Streptomyces lividans, for which a crystal structure of the 

Use of this particular pharmacophore in subsequent 3D database searching of about 1 million compounds resulted in 244 interesting compounds, from which 19 compounds showed IC50 values below 10 pM. 

IC5O=0.9 fiM H2610, ICso=7.7 pM U8203, IC50=7.9 pM 

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Fig. 19.11 Scheme for a structure-based biophysical screening for lead finding. 

This chapter has reviewed the basic principles of computer-aided drug design, and several strategies of how it can be successfully integrated with combinatorial chemistry to develop highly effective site-focused libraries. Diversity plays a key role, as the more diverse set of compounds tested that fit the site-focused criteria, the more information is retrieved to improve the site-focused definition, which further directs the search in diversity space. In addition, if good hits are found, the information can be fed back to find compounds close in diverse space to the hit. This new paradigm for structure-based combinatorial chemistry should provide a powerful tool for rapid discovery of novel, potent lead compounds in the years to come. 

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