Substituent ordering and interpolation in molecular library optimization

The substituent ordering problem in molecular libraries refers to identifying a rational ordering for molecular moieties such that coarse sampling and interpolation over the full space of possible library molecules may be efficiently performed. A practical solution to the ordering problem is proposed on the bases of (a) coarse sampling of the molecular substituents, (b) radial basis function interpolation over the full space, and (c) the use of genetic algorithms to find rational moiety orderings. The procedure is shown to be extremely effective for a variety of simulated libraries. This algorithm is also used to reorder and predict the glass transition temperature T_g for a combinatorial polymer library.