Challenges and prospects for computational aids to molecular diversity

Although workers have devised many usable strategies, a validated method for the computational analysis and optimization of molecular diversity in compound collections or combinatorial libraries remains a challenge. Even the most ambitious programs consider less than 1:1039 of all possible compounds. The various methods need to be validated against experimental data and compared with each other, which might require sharing the structures and biological activities of 105–106 molecules. We need molecular descriptors that more accurately reflect the biological properties of compounds: this will probably entail designing a strategy to realistically include the properties of the multiple conformers, tautomers, and ionization states of molecules. For true computer generation of diverse synthesizable compounds, we need a whole new generation of programs that organize the knowledge of synthetic organic 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.