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.

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.

As with many other rules of thumb, such as Baldwin's rules for ring closure, there are many exceptions.

Variants

In an attempt to improve the predictions of druglikeness, the rules have spawned many extensions, for example the Ghose filter: In particular, compounds which meet only the two criteria of:

  • 10 or fewer rotatable bonds and
  • Polar surface area no greater than 140 Å<sup>2</sup>

are predicted to have good oral bioavailability.

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