Rational Combinatorial Library Design. 1. Focus-2D: A New Approach to the Design of Targeted Combinatorial Chemical Libraries

A strategy for rational design of targeted combinatorial libraries is described. The aim of this approach is to select a subset of available building blocks for the library synthesis that are most likely to be present in the active compounds. Building blocks that are used in the underlying combinatorial chemical reaction are randomly assembled to produce virtual combinatorial library compounds, which are represented by various chemical descriptors. Stochastic algorithms (simulated annealing, genetic algorithms, neural net methods) are used to search the potentially large structural space of virtual chemical libraries in order to identify compounds similar to lead compound(-s). The selection of a virtual molecule as a candidate for the targeted library is based either on its chemical similarity to a biologically active probe or on its biological activity predicted from a pre-constructed QSAR equation. Frequency analysis of building block composition of the selected virtual compounds identifies building blocks that can be used in combinatorial synthesis of chemical libraries with high similarity to the lead compound(-s). This method is applied to rational design of the library with bradykinin potentiating activity. Twenty eight bradykinin potentiating pentapeptides were used as a training set for the development of a QSAR equation, and, alternatively, two active pentapeptides, VEWAK and VKWAP, were used as probe molecules. In each case, the frequency distribution of amino acids in the top 100 peptides suggested by the method resembles the frequency distribution of amino acids found in the active peptides. The results obtained after GA optimization also compared favorably with those obtained by the exhaustive analysis of all possible 3.2 millions pentapeptides.