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.