Designing novel nicotinic agonists by searching a database of molecular shapes

Summary We introduce an approach by which novel ligands can be designed for a receptor if a pharmacophore geometry has been established and the receptor-bound conformations of other ligands are known. We use the shape-matching method of Kuntz et al. J. Mol. Biol., 161 (1982) 269–288] to search a database of molecular shapes for those molecules which can fit inside the combined volume of the known ligands and which have interatomic distances compatible with the pharmacophore geometry. Some of these molecules are then modified by interactive modeling techniques to better match the chemical properties of the known ligands. Our shape database (about 5000 candidate molecules) is derived from a subset of the Cambridge Crystallographic Database Allen et al., Acta Crystallogr., Sect. B,35 (1979) 2331–2339]. We show, as an example, how several novel designs for nicotinic agonists can be derived by this approach, given a pharmacophore model derived from known agonists Sheridan et al., J. Med. Chem., 29 (1986) 889–906]. This report complements our previous report DesJarlais et al., J. Med. Chem., in press], which introduced a similar method for designing ligands when the structure of the receptor is known.