In a specific embodiment, this invention includes a method for determining an accurate,
consensus pharmacophore structure shared by compounds that bind selectively to a target molecule. Optionally, the method begins with screening a diversity
library against the target molecule of interest to pick the selectively binding members. Next the structure of the selected members is examined and a candidate
pharmacophore responsible for the binding to the target molecule is determined. Next, preferably by REDOR
nuclear magnetic resonance, several highly accurate interatomic distances are determined in certain of the selected members which are related to the candidate
pharmacophore. A highly accurate
consensus, configurational bias, Monte Carlo method determination of the structure of the candidate pharmacophore is made using the structure of the selected members and incorporating as constraints the shared candidate pharmacophore and the several measured distances. This determination is adapted to efficiently examine only relatively low energy configurations while respecting any structural constraints present in the organic diversity
library. If the diversity
library contains short peptides, the determination respects the known
degrees of freedom of peptides as well as any internal constraints, such as those imposed by disulfide bridges. Finally, the highly accurate pharmacophore so determined is used to select lead organics for
drug development targeted at the initial target molecule.