CHALLENGES AND PROSPECTS FOR COMPUTATIONAL AIDS TO MOLECULAR DIVERSITY

Although workers have devised many usable strategies, a validated meth od for the computational analysis and optimization of molecular divers ity in compound collections or combinatorial libraries remains a chall enge. Even the most ambitious programs consider less than 1:10(39) of all possible compounds. The various methods need to be validated again st experimental data and compared with each other, which might require sharing the structures and biological activities of 10(5)-10(6) molec ules. We need molecular descriptors that more accurately reflect the b iological properties of compounds: this will probably entail designing a strategy to realistically include the properties of the multiple co nformers, tautomers, and ionization states of molecules. For true comp uter generation of diverse synthesizable compounds, we need a whole ne w generation of programs that organize the knowledge of synthetic orga nic chemistry. Additionally, if the goal is to design molecules to fit a macromolecular target of known 3D structure, we also need improved methods for estimating ligand affinity.