View source for Lipinski's Rule of Five

{{Mergeto|Druglikeness|date=April 2007}}

'''Lipinski's Rule of Five''' is a [[rule of thumb]] to evaluate [[druglikeness]], or determine if a [[chemical compound]] with a certain [[pharmacology|pharmacological]] or [[biological activity]] has properties that would make it a likely [[oral activity|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 [[lipophilicity|lipophilic]] [[molecule]]s.<ref>C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, ''Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings'', Adv. Drug Del. Rev., '''2001''', ''46'', 3-26. ({{DOI|10.1016/S0169-409X(00)00129-0}})</ref>

The rule describes [[molecular property|molecular properties]] important for a drug's [[pharmacokinetics]] in the human body, including their [[absorption (pharmacokinetics)|absorption]], [[distribution (pharmacology)|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 [[Drug discovery hit to lead|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 [[chemical bond|bonds]], and a higher lipophilicity.<ref>T. I. Oprea, A. M. Davis, S. J. Teague, P. D. Leeson, ''Is There a Difference between Leads and Drugs? A Historical Perspective'', J. Chem. Inf. Comput. Sci., '''2001''', ''41'', 1308-1315.</ref>

==The rule==
Lipinski's Rule of Five states that, in general, an orally active drug has:
* Not more than 5 [[hydrogen bond]] donors (OH and NH groups)
* Not more than 10 hydrogen bond acceptors (notably [[nitrogen|N]] and [[oxygen|O]])
* 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.:<ref>Arup K. Ghose, Vellarkad N. Viswanadhan, and John J. Wendoloski, ''A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery'', J. Combin. Chem., '''1999''', ''1'', 55-68. ({{DOI|10.1021/cc9800071}})</ref>
* 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==
{{reflist|2}}

==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

[[Category:Medicinal chemistry]]
[[Category:Pharmacology]]
[[Category:Cheminformatics]]
[[Category:Drug discovery]]

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