During drug discovery, lipophilicity and molecular weight are often increased in order to improve the affinity and selectivity of the drug candidate.  Hence it is often difficult to maintain drug-likeness (i.e., RO5 compliance) during hit and lead optimization.  Hence it has been proposed that members of screening libraries from which hits are discovered should be biased toward lower molecular weight and lipophilicity so that medicinal chemists will have an easier time in delivering optimized drug development candidates that are also drug-like. Hence the rule of five has been extended to the rule of three (RO3) for defining lead-like compounds.
A rule of three compliant compound is defined as one that has:
* octanol-water partition coefficient log P not greater than 3
* molecular mass less than 300 daltons
* not more than 3 hydrogen bond donors
* not more than 3 hydrogen bond acceptors
* not more than 3 rotatable bonds