In 1997 Christopher Lipinski and colleagues looked at the physicochemical characteristics of approved drugs and clinical candidates at that time, and proposed that the 'rule of 5' could predict the likelihood that a given small molecule will be orally active. This guideline prioritized compounds that have molecular masses of less than 500 daltons, calculated logarithm of the octanol−water partition coefficient (clogP) of less than 5, 5 or fewer hydrogen bond donors, and 10 or fewer hydrogen bond acceptors — and red flagged compounds that have more than one parameter out of range. Novartis's Michael Shultz now argues that this drug-likeness rule of thumb does not stand the test of time.

Reporting in the Journal of Medicinal Chemistry, Shultz assessed the physicochemical properties of the 409 small molecules that the FDA has approved since 1997. Molecular mass in this cohort has increased considerably from the baseline, he found, and in both 2016 and 2017 the average molecular mass of FDA-approved drugs was greater than 500 daltons. An up-to-date molecular mass cut-off based on the properties of orally available small molecules approved in the past decade would now be more than 600 daltons, he found. The threshold for hydrogen bond acceptors has also increased substantially.

These data call into question the hypothesis that 'drug-like' properties exist, he concludes. “Repeating the [rule of 5] experiment today, with over twice as many oral drugs approved than were available in 1997, gives different 'rules' than those hypothesized two decades ago ... If our past future predictions have not been accurate with the [rule of 5] parameters, we must call into question our current future predictions.”

With new modalities coming online — such as targeted protein degraders and constrained peptides — he urges drug developers to reconsider how they use the rule of 5. “We are in danger of repeating our past mistakes if we assume these new modalities are not 'drug-like' and cannot be oral drugs because they are not [rule of 5] compliant,” writes Shultz.