What is the rule of five, and how should it be used?

Why

Lipinski and colleagues derived the rule from compounds that had reached late development, so it describes what orally absorbed molecules have tended to look like. Each property relates to the physical problem of crossing a membrane while staying soluble. Many donors and acceptors mean strong interaction with water and a cost to entering the lipid interior.

High logP means poor solubility. High molecular weight means slow permeation. The same paper noted that screening hits tend to be larger and greasier than pre-screening-era leads, which is why starting points matter.

The common misuse is to treat the rule as a pass or fail test. It explicitly allows exceptions, including compounds that use active transport, and whole classes sit outside it, including natural products, peptides, antibiotics and most biologics. It also says nothing about potency, selectivity, metabolic stability, toxicity or whether the target is reachable.

It applies to oral absorption only. An inhaled, injected or topical drug has different constraints. In practice it is useful early, to notice that a series is drifting toward higher weight and lipophilicity as potency is optimized, which is a known trap.