Lipinski's rule of five

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Lipinski's rule of five (RO5) is a simple guideline to help predict if a chemical compound could become an orally active drug in humans. It was introduced by Christopher Lipinski in 1997 after noting that most oral drugs are small and moderately lipophilic, which relates to how the compound is absorbed and handled by the body (ADME: absorption, distribution, metabolism, excretion).

Key idea
- A drug is more likely to be orally active if it meets these four criteria, with at most one violation:
- Molecular weight (MW) ≤ 500
- LogP (lipophilicity) ≤ 5
- No more than 5 hydrogen bond donors
- No more than 10 hydrogen bond acceptors

Important caveats
- The rule does not predict whether a compound is pharmacologically active.
- Not all drugs follow the rule, and about half of new oral drugs do.
- Some natural products, such as macrolides and peptides, break the rules.
- Transporters and other cellular uptake mechanisms can play a big role in drug absorption, not just passive diffusion.

Extensions and refinements
- To improve predictions, researchers have developed additions like the Ghose filter and Veber rules.
- Veber’s criteria emphasize other factors for oral bioavailability, such as polar surface area (PSA) and the number of rotatable bonds.

Lead-like idea
- For screening, many teams use a tighter standard (RO3), aiming for smaller, simpler molecules that are easier to optimize into drug-like candidates.

Bottom line
RO5 is a useful, rough guide to steer early drug design toward compounds more likely to be orally available, but it’s not a strict rule and there are many exceptions.