Targeted library design

Miller J L (2006). Recent developments in focused library design Targeting gene-families. Curr. Topics Med. Chem. 6 19-29. 

Miller, J.L. (2006) Recent developments in focused library design targeting gene-families. Current Topics in Medicinal Chemistry, 6, 19-29. 

W Zheng, SI Cho, A Tropsha. Rational combinatorial library design 1. Focus-2D A new approach to the design of targeted combinatorial chemical libraries. J Chem Inf Comput Sci 38 251-258, 1998. 

Andrews KM, Cramer RD. Toward general methods of targeted library design topomer shape similarity searching with diverse structures as queries. / Med Chem 2000 43 1723-40. 

Library designed, on the basis of preexisting information, to generate enhanced activity or hit rate against a particular biological target or target class. 

Targeted libraries have been most effective when based upon the display of diverse functionality about a minimal mechanism-based pharmacophore targeting an enzyme family. Early successes with this approach were first achieved with proteases.1221 Our own efforts to design libraries which target enzyme families require that the minimal pharmacophore serves as the site for attachment to solid support.1231 The pharmacophore is the only invariant part of the inhibitor structure, which... 

Combinatorial approaches have been most successful when information about the target biomole cule has been considered in the design of the library. However, for many biomolecules, structural or mechanistic information is not available or does not provide sufficient insight to enable productive library design Also, lead compounds are not available for many targets, and in some cases, novel motifs for binding are desired. Under these circumstances, it is no surprise that the successful application of combinatorial chemistry has been less fre-... 

For targets without leads, a lead generation approach is employed if work on such a target is to continue. Such approaches usually require the construction of small-molecule libraries in order to maximize the chances of finding compounds of some level of minimal potency necessary to identify a hona fide lead useful for further optimization. Lead generation library design should emphasize design quality of the individual molecules over their numbers. This topic has been discussed extensively [12]. 

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