Lipinski's rule of five
rule of thumb that a compound is likely orally active if it violates at most one of: ≤5 hydrogen bond donors; ≤10 hydrogen bond acceptors; molecular mass of ≤500 Da; octanol-water partition coefficient of ≤5
Lipinski's rule of five, also known as Pfizer's rule of five or simply the rule of five (RO5), is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would likely make it an orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most orally administered drugs are relatively small and moderately lipophilic molecules.
The rule describes molecular properties important for a drug's pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion ("ADME"). However, the rule does not predict if a compound is pharmacologically active.
The rule is important to keep in mind during drug discovery when a pharmacologically active lead structure is optimized step-wise to increase the activity and selectivity of the compound as well as to ensure drug-like physicochemical properties are maintained as described by Lipinski's rule. Candidate drugs that conform to the RO5 tend to have lower attrition rates during clinical trials and hence have an increased chance of reaching the market.
Some authors have criticized the rule of five for the implicit assumption that passive diffusion is the only important mechanism for the entry of drugs into cells, ignoring the role of transporters. For example, O'Hagan and co-authors wrote as follows:This famous "rule of 5" has been highly influential in this regard, but only about 50 % of orally administered new chemical entities actually obey it.
Studies have also demonstrated that some natural products break the chemical rules used in Lipinski filters such as macrolides and peptides.
Components of the rule
Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria:
No more than 5 hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds)
No more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms)
A molecular mass less than 500 daltons
A calculated octanol-water partition coefficient (Clog P) that does not exceed 5
Note that all numbers are multiples of five, which is the origin of the rule's name.
Begin with the source’s own compact description: “Lipinski's rule of five” is rule of thumb that a compound is likely orally active if it violates at most one of: ≤5 hydrogen bond donors; ≤10 hydrogen bond acceptors; molecular mass of ≤500 Da; octanol-water partition coefficient of ≤5. The dossier treats that line as a proposition to test through Lipinski's, rule and five, not as a finished interpretation.
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The citation trail is more important than the brevity of the summary: it shows where individual claims can be examined in context. The source revision retrieved here is dated Aug 11, 2026. The linked authority identifier is Q916723. None of the 0 selected statements returned an explicit reference. The first chronological checks are 1997.
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