Molecular complexity and its impact on the probability of finding leads for drug discovery

Using a simple model of ligand-receptor interactions, the interactions betw een ligands and receptors of varying complexities are studied and the proba bilities of binding calculated. It is observed that as the systems become m ore complex the chance of observing a useful interaction for a randomly cho sen ligand falls dramatically. The implications of this for the design of c ombinatorial libraries is explored. A large set of drug leads and optimized compounds is profiled using several different properties relevant to molec ular recognition. The changes observed for these properties during the drug optimization phase support the hypothesis that less complex molecules are more common starting points for the discovery of drugs. An extreme example of the use of simple molecules for directed screening against thrombin is p rovided.