Library design pharmacophores

McGregor, M. J., Muskal, S. M. Pharmacophore fingerprinting. 2. Application to primary library design. 

Pickett, S.D., Luttmann, C., Guerin, V., Laoui, a., and JAMES, E. DIVSEL and COM PEI B - strategies for the design and comparison of combinatorial libraries using pharmacophoric descriptors. 

Mason, J.S. and Cheney, D.L. Library design and virtual screening using multiple 4-point pharmacophore fingerprints. Pac. Symp. Biocomput. 1999, 4, 456-467. 

Mason, J.S. and Beno, B.R. Library design using BCUT chemistry-space descriptors and multiple four-point pharmacophore fingerprints simultaneous optimization and structure-based diversity. /. Mol. 

Davies, K. and Briant, C. Combinatorial chemistry library design using pharmacophore diversity. Netw. Sci. 1995, 1. Available at URL http //www.awod.com/netsci/lssues/ July95 /feature6.html. 

Fig. 15.25 Partial display of virtual screen of conformational ensemble of " 75 000 structure library based on multiple templates. A display of fitness scores to a three-point pharmacophore model provides initial signs of similarity of a library design to that model. Subsequent virtual screening against a more stringent four-point pharmacophore model further highlights potentially useful library designs.

Quantitative Structure-Activity Relationship models are used increasingly in chemical data mining and combinatorial library design [5, 6]. For example, three-dimensional (3-D) stereoelectronic pharmacophore based on QSAR modeling was used recently to search the National Cancer Institute Repository of Small Molecules [7] to find new leads for inhibiting HIV type 1 reverse transcriptase at the nonnucleoside binding site [8]. A descriptor pharmacophore concept was introduced by us recently [9] on the basis of variable selection QSAR the descriptor pharmacophore is defined as a subset of... 

Mason and coworkers reported one of the first examples of a target class library design utilizing 3D pharmacophore descriptors (20). In this example, the authors designed a set of GPCR-targeted libraries based on Ugi chemistry... 

Other approaches that could be extended to target class library design include work by McGregor and Muskal (13,19). These utilized PharmPrint 3D pharmacophore descriptors (three-point pharmacophores) and partial least... 

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... 

Beno, B. R. and Mason, J. S. Combinatorial library design using both properties and 3D pharmacophore fingerprints. Book of Abstracts, 221st ACS National Meeting, San Diego, 2001. 

Eksterowicz, J. E., Evensen, E., Lemmen, C., et al. (2002) Coupling structure-based design with combinatorial chemistry application of active site derived pharmacophores with informative library design. J. Mol. Graph. Model. 20, 469-477. 

Afifymax s thiolacyl library (Fig. 1.9) and Pharmacopeia s statine library (Fig. 1.10) are pharmacophore-based libraries however, their design is different. In the former library, a pool of advanced library intermediates are derivatized with the pharmacophore (thiolacylation) as the final step in library construction, while in the latter library the pharmacophore (statine) is derivatized with synthons as part of library construction. 

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