| 愚者不惑也 |
2011-02-28 22:37 |
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 all and lipophilic molecules.[1]
The rule describes molecular properties important for a drug's pharmacokinetics in the human body, including their absorption, distribution, metaboli, 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 log P of less than 5
Note that all numbers are multiples of five, which is the origin of the rule's name.
To evaluate druglikeness better, the rules have spawned many extensions, for example one from a 1999 paper by Ghose et al.:[3]
• 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 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
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