Lipinski's Rule of Five

Lipinski's Rule of Five is a rule of thumb to evaluate druglikeness, or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most medication drugs are relatively small and lipophilic molecules. [cite journal | author = C.A. Lipinski; F. Lombardo; B.W. Dominy and P.J. Feeney | title = Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings | journal = Adv Drug Del Rev | year = 1997 | volume = 23 | pages = 3–25 | doi = 10.1016/S0169-409X(00)00129-0]

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 for drug development where a pharmacologically active lead structure is optimized step-wise for increased activity and selectivity, as well as drug-like properties as described by Lipinski's rule. The modification of the molecular structure often leads to drugs with higher molecular weight, more rings, more rotatable bonds, and a higher lipophilicity. [cite journal | author = T. I. Oprea, A. M. Davis, S. J. Teague, P. D. Leeson | title = Is There a Difference between Leads and Drugs? A Historical Perspective | journal = J. Chem. Inf. Comput. Sci. | year = 2001 | volume = 41 | pages = 1308–1315 | doi = 10.1021/ci010366a]

The rule

Lipinski's Rule of Five states that, in general, an orally active drug has no more than one violation of the following criteria:

* Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
* Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)
* A molecular weight under 500 g/mol
* A partition coefficient log "P" less than 5

Note that all numbers are multiples of five, which is the origin of the rule's name.

Improvements

To evaluate druglikeness better, the rules have spawned many extensions, for example one from a 1999 paper by Ghose et al.: [cite journal | author = Arup K. Ghose, Vellarkad N. Viswanadhan, and John J. Wendoloski | title = A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery | journal = J. Combin. Chem. | year = 1999 | volume = 1 | pages = 55–68 | doi = 10.1021/cc9800071]

* Partition coefficient log "P" in -0.4 to +5.6 range
* Molar refractivity from 40 to 130
* Molecular weight from 160 to 480
* Number of heavy atoms from 20 to 70

Over the past decade Lipinski's profiling tool for druglikeness has led to further investigations by scientists to extend profiling tools to lead-like properties of compounds in the hope that a better starting point in early discovery can save time and cost.

See also

* QSAR, quantitative structure-activity relationship
* Polar surface area
* Biopharmaceutics Classification System
* Chemical property
* Molecular property
* Physical property
* Chemical structure

References

External links

* [http://www.molinspiration.com/cgi-bin/properties Interactive Rule of Five calculator]
* [http://www.chemaxon.com/demosite/marvin/index.html Free online calculations of Hydrogen bond donor/acceptor, mass and logP] using ChemAxon's Marvin and Calculator Plugins - requires Java