Site-directed library design

Fig. 4,13 Illustration of the protein site-directed library design protocol of Eksterowicz and coworkers [149], Starting with the protein structure, a site map is generated from the active site. Pharmacophores are enumerated and used to define the space for library design. Compounds are then selected with the...

The receptor relevance of BCUT descriptors has inspired several groups to apply them in conjunction with other methods. Beno and Mason reported the use of simulated annealing to optimize library design using BCUT chemistry space and four-point pharmacophores concurrently (33) and the use of chemistry spaces in conjunction with property profiles (52). The application of such composite methods to target class library design is readily apparent. Pirard and Pickett reported the application of the chemometric method, partial least squares discriminant analysis, with BCUT descriptors to successfully classify ATP-site-directed kinase inhibitors active against five different protein kinases... 

Fig. 8. CDK4 selective library design process of Honma et al. (64). (A) Align sequences of 390 kinases. Dark circles denote residues with <40% conservation or subject to replacement in CDK1/2/6. (B) Darker residues in ATP binding site pinpoint the least conserved residues highlighted in (A). (C) Map lead structure onto difference residues. Arrows denote direction and distance to said amino acids. (D) Design library according to these constraints. Resulting compounds show up to 180-fold selectivity for CDK4 with respect to CDK2. Adapted from ref. 64.

Gehlhaar, D. K., Bouzida, D., and Rejto, P. A. (1999) Reduced dimensionality in ligand-protein structure prediction covalent inhibitors of serine proteases and design of site-directed combinatorial libraries. ACS Symposium Series 719, 292-311. 

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. 

Pharmacophore fingerprints generated from complementary site points can be used to direct combinatorial library design and to investigate selectivity. An example of the pharmacophore fingerprinting method for selectivity studies has been validated (37a,b) in studies of three closely related serine proteases thrombin, Factor Xa, and trypsin. Site points were... 

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