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.[1]
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.[2]
Lipinski's rule says 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 daltons
- An octanol-water partition coefficient[3] log P of less than 5
Note that all numbers are multiples of five, which is the origin of the rule's name.
Contents
[hide]Improvements
To evaluate druglikeness better, the rules have spawned many extensions, for example one from a 1999 paper by Ghose et al.:[4]
- Partition coefficient log P in -0.4 to +5.6 range
- Molar refractivity from 40 to 130
- Molecular weight from 160 to 500
- 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])
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. Some compound searching sites, such as the extensive searching tools on the ASDI website, now allow using Rule-of-5 and other properties to rapidly identify compounds that may be more desireable for high throughput screening and for parallel synthesis efforts[5]
See also
- QSAR, quantitative structure-activity relationship
- Polar surface area
- Biopharmaceutics Classification System
- Chemical property
- Molecular property
- Physical property
- Chemical structure
References
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External links
- Interactive Rule of Five calculator
- Free online calculations of Hydrogen bond donor/acceptor, mass and logP using ChemAxon's Marvin and Calculator Plugins - requires Java
- Calculation of Druglikeness - requires Javaca:Regla del Cinc de Lipinski
de:Rule of Five es:Regla de cinco de Lipinsky it:Regola di Lipinski ja:リピンスキーの法則 sl:Pravilo Lipinskega sv:Lipinskis fem regler
zh:里宾斯基五规则- Jump up ↑ C.A. Lipinski; F. Lombardo; B.W. Dominy and P.J. Feeney (1997). "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings". Adv Drug Del Rev. 23: 3–25. doi:10.1016/S0169-409X(00)00129-0.
- Jump up ↑ T. I. Oprea, A. M. Davis, S. J. Teague, P. D. Leeson (2001). "Is There a Difference between Leads and Drugs? A Historical Perspective". J. Chem. Inf. Comput. Sci. 41: 1308–1315. doi:10.1021/ci010366a.
- Jump up ↑ Leo A, Hansch C, and Elkins D (1971). "Partition coefficients and their uses". Chem Rev. 71 (6): 525–616. doi:10.1021/cr60274a001.
- Jump up ↑ Arup K. Ghose, Vellarkad N. Viswanadhan, and John J. Wendoloski (1999). "A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery". J. Combin. Chem. 1: 55–68. doi:10.1021/cc9800071.
- Jump up ↑ Michael Wagaman, Greg Silber, et al., ASDI, (2008), see http://web.asdi.net/index.php/online-ordering-system