Designing Active Template Molecules by Combining Computational De Novo Design and Human Chemist's Expertise

We used a new software tool for de novo design, the “Molecule Evoluator”, to generate a number of small
molecules. Explicit constraints were a relatively low molecular weight and otherwise limited functionality,
for example, low numbers of hydrogen bond donors and acceptors, one or two aromatic rings, and a small
number of rotatable bonds. In this way, we obtained a collection of scaffold- or templatelike molecules
rather than fully “decorated” ones. We asked medicinal chemists to evaluate the suggested molecules for
ease of synthesis and overall appeal, allowing them to make structural changes to the molecules for these
reasons. On the basis of their recommendations, we synthesized eight molecules with an unprecedented
(not patented) yet simple structure, which were subsequently tested in a screen of 83 drug targets, mostly
G protein-coupled receptors. Four compounds showed affinity for biogenic amine targets (receptor, ion
channel, and transport protein), reflecting the training of the medicinal chemists involved. Apparently the
generation of leadlike solutions helped the medicinal chemists to select good starting points for future lead
optimization, away from existing compound libraries.