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.[2]
Lipinski's rule 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 mass less than 500 daltons
- An octanol-water partition coefficient[3] log P not greater than 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 guidelines for ring closure or Murphy's guidelines), there are many exceptions to Lipinski's Rule.
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[edit] 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])
- Polar surface area no greater than 140 Ǻ2
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 desirable for high throughput screening and for parallel synthesis efforts.[5]
[edit] See also
- QSAR, quantitative structure-activity relationship
- Polar surface area
- Biopharmaceutics Classification System
- Chemical property
- Molecular property
- Physical property
- Chemical structure
- Chemicalize.org: List of predicted structure based properties
[edit] References
- ^ C.A. Lipinski; F. Lombardo; B.W. Dominy and P.J. Feeney (2001). "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings". Adv Drug Del Rev 46: 3–26. doi:10.1016/S0169-409X(00)00129-0. PMID 11259830.
- ^ 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 (5): 1308–1315. doi:10.1021/ci010366a.
- ^ Leo A, Hansch C, and Elkins D (1971). "Partition coefficients and their uses". Chem Rev 71 (6): 525–616. doi:10.1021/cr60274a001.
- ^ 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. PMID 10746014.
- ^ Michael Wagaman, Greg Silber, et al., ASDI, (2008), see http://web.asdi.net/index.php/online-ordering-system
[edit] 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 Java
