Lead compounds library design

The identification of Gdk4-specific amino acid residues allowed us to focus on target residues that interact with substituents on lead compounds. Library design based on the locations of these residues and the binding modes of lead compounds enabled us to develop potent and selective compounds efficiently. Among them, compound 11 showed excellent selectivity not only over Cdkl/2 (780-fold/... 

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]. 

Basic formulation The problem of selecting lead compounds for lead-generation library design can be stated in general as follows Given a distribution ofN compounds, , in a descriptor space L2, find the set of M lead compounds, rh that solves the following... 

Compound libraries designed for the identification of new lead structures should not contain large numbers of closely related compounds (which are likely to have similar properties), but highly diverse compounds with widely different properties. Because compound libraries are prepared using the same reaction sequence for each... 

The discovery of this lead compound as a potent PDF inhibitor was a result of an integrated combinatorial and medicinal chemistry approach based on the proposed generic PDF inhibitor structure. This focused chemical library was designed by Chen et al. [79], and was prepared using solid-phase parallel synthesis in which 22 amines and 24 amino acids were used as building blocks, as outlined in Scheme 23. 

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