PLUMS: a program for the rapid optimization of focused libraries

PLUMS is a new method to perform rational monomer selection for combinatori al chemistry libraries. The algorithm has been developed to optimize focuse d libraries with specific two-dimensional and/or three-dimensional properti es. A preliminary step is the identification of those molecules in the init ial virtual library which satisfy the imposed property constraints; we defi ne these molecules as the virtual hits. From the virtual hits, PLUMS genera tes a starting library,which is the true combinatorial library that include s all the virtual hits. Monomers are then removed in an iterative fashion, thus reducing the size of the library. At each iteration, the worst monomer is removed. Each sublibrary is selected using a global scoring function, w hich balances effectiveness and efficiency. The iterative process continues until one is left with a library that consists entirely of virtual hits. T he optimal library, which is the best compromise between effectiveness and efficiency, can then be selected. according to the score. During the iterat ive process, equivalent solutions may well occur and are taken into account by the algorithm, according to a user-defined parameter. The number of mon omers for each substitution site and the size of the library are parameters that can be either optimized or used to constrain the selection. The resul ts obtained on two test libraries are presented. PLUMS was compared with ge netic algorithms (GA) and monomer frequency analysis (MFA), which are widel y used for monomer selection. For the two test libraries, PLUMS and GA gave equivalent results. MFA is the fastest method, but it can give misleading solutions. Possible advantages and disadvantages of the different methods a re discussed.