Lipinski's rule of five, also known asPfizer's rule of five or simply therule of five (RO5), is arule of thumb to evaluatedruglikeness or determine if achemical compound with a certainpharmacological orbiological activity haschemical properties andphysical properties that would likely make it anorally active drug in humans. The rule was formulated byChristopher A. Lipinski in 1997, based on the observation that most orally administered drugs are relativelysmall and moderatelylipophilicmolecules.^[1][2]

The rule describesmolecular properties important for a drug'spharmacokinetics in the human body, including theirabsorption,distribution,metabolism, andexcretion ("ADME"). However, the rule does not predict if a compound is pharmacologically active.

The rule is important to keep in mind duringdrug discovery when a pharmacologically activelead 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.^[3] Candidate drugs that conform to the RO5 tend to have lower attrition rates duringclinical trials and hence have an increased chance of reaching the market.^[2][4]

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:^[5]

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.^[6][7][8]

Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria:^[9]

• No more than 5hydrogen bond donors (the total number ofnitrogen–hydrogen andoxygen–hydrogenbonds)
• No more than 10hydrogen bond acceptors (allnitrogen oroxygenatoms)
• Amolecular mass less than 500daltons
• A calculatedoctanol-water partition coefficient (ClogP) that does not exceed 5

Note that all numbers are multiples of five, which is the origin of the rule's name.As with many otherrules of thumb, such asBaldwin's rules for ring closure, there are many exceptions.

In an attempt to improve the predictions ofdruglikeness, the rules have spawned many extensions, for example the Ghose filter:^[10]

• Partition coefficient logP in −0.4 to +5.6 range
• Molar refractivity from 40 to 130
• Molecular weight from 180 to 480
• Number of atoms from 20 to 70 (includes H-bond donors [e.g. OHs and NHs] and H-bond acceptors [e.g. Ns and Os])

Veber's Rule further questions a 500 molecular weight cutoff. Thepolar surface area and the number of rotatable bonds has been found to better discriminate between compounds that are orally active and those that are not for a large data set of compounds.^[11] In particular, compounds which meet only the two criteria of:

• 10 or fewer rotatable bonds and
• Polar surface area no greater than 140 Ų

are predicted to have good oral bioavailability.^[11]

During drug discovery, lipophilicity and molecular weight are often increased in order to improve the affinity and selectivity of the drug candidate. Hence it is often difficult to maintain drug-likeness (i.e., RO5 compliance) during hit and lead optimization. Hence it has been proposed that members ofscreening libraries from which hits are discovered should be biased toward lower molecular weight and lipophilicity so that medicinal chemists will have an easier time in delivering optimized drug development candidates that are also drug-like. Hence the rule of five has been extended to therule of three (RO3) for defininglead-like compounds.^[12]

A rule of three compliant compound is defined as one that has:

• octanol-waterpartition coefficient logP not greater than 3
• molecular mass less than 300daltons
• not more than 3hydrogen bond donors
• not more than 3hydrogen bond acceptors
• not more than 3 rotatable bonds

• Biopharmaceutics Classification System
• Chemical structure
• Chemicalize.org § List of the predicted structure based properties
• Fragment-based lead discovery
• QSAR

• Free online calculations of Hydrogen bond donor/acceptor, mass and logP usingChemAxon's Marvin and Calculator Plugins – requires Java
• Calculation of Druglikeness – requires Java

• Medicinal chemistry
• Drug development
• Cheminformatics
• Drug discovery
• Rules of thumb

• Articles with short description
• Short description is different from Wikidata
• Use dmy dates from September 2020