Lipinski's rule of five

Lipinski's rule of five is a famous back-of-the-envelope checklist for guessing whether a molecule has a fair chance of being absorbed when taken as a pill. Christopher Lipinski distilled it in 1997 from patterns across thousands of marketed oral drugs, and it became a quick mental filter for chemists everywhere.

Poor oral absorption becomes more likely when a molecule breaks more than one of four limits: molecular weight above 500, logP above 5, more than 5 hydrogen-bond donors, and more than 10 hydrogen-bond acceptors. The recurring fives are why it is called the rule of five. All four thresholds are multiples of five.

It is a guideline, not a law of nature, and it has well-known blind spots. It says nothing about potency, metabolism, or toxicity; it does not apply to actively transported molecules or to natural products and many biologics; and successful drugs (including some kinase inhibitors and macrocycles) routinely violate it. Modern practice treats it as one input among several, alongside polar surface area, rotatable bonds, and overall druglikeness.