Computer design of potentially bioactive molecules by geometric searching with ALADDIN

Structurally novel potential dopamine agonists were designed by searching databases of 3D structures to find templates that match geometric criteria and can be modified into molecules suggested for synthesis. A search of 54,296 3D structures from three different databases generated 499 structurally unique molecules that meet our geometric criteria for D-2 dopaminergic activity. The search identified 8 of 9 classes of known fused ring phenolic dopaminergic compounds and 62 other classes of fused ring compounds with potential activity. The low observed frequency of finding the same ring class more than once suggests that additional searches will design many additional molecules. Compound design based on 3D substructure searching methods appears to be equally applicable to suggesting new classes of compounds for beginning or for mature medicinal chemistry investigations and does not require the construction of special libraries of templates.