A dual fingerprint-based metric for the design of focused compound libraries and analogs

A computational metric is introduced for the design of combinatorial librar ies focused on small molecules with specific activity (e.g., enzyme inhibit ors). The method follows a product-based design strategy and uses combinati ons of two binary molecular fingerprints to create chemical diversity aroun d selected compounds and/or core structures. In the first step, compounds a re sampled that are distinct from template molecules but likely to share si milar biological activity. In the second step, designed compounds are accep ted if they are not too similar to each other, as assessed by calculation o f fingerprint overlap. Thus, it is possible to balance molecular "similarit y" and "diversity" and control the degree of chemical diversity created in the vicinity of selected template molecules. In essence, the method aims to generate diverse arrays of compounds with a high probability of having act ivity similar to starting molecule(s) and is therefore well suited for the design of target-focused libraries or series of analogs. As an example, the method is applied to focus libraries on known protein kinase inhibitors.