Lipinski's Rule of Five

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In 1997 Christopher A. Lipinski published a seminal paper identifying a series of features commonly found in orally active drugs. ^[1] These features are referred to as Lipinski's rule of five and can be used as a rule of thumb to indicate whether a molecule is likely to be orally bioavailable (bioactive) (See also ADME). The "rule of five" is so called because most of the features start with the number five.

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 N and O)
A molecular weight under 500
A partition coefficient log P under 5

There are two typical misunderstandings with this rule of thumb.

Molecules that possess this rule are not automatically drug-like. For classifying a molecule as drug-like or non-drug-like a proper cheminformatic approach should be used, e.g. QSAR.
This rule was derived for drugs and not for lead structures, which usually have a lower molecular weight, fewer rings, fewer rotatable bonds, and a lower lipophilicity.^[2]

The rules have spawned many extensions, for example these from 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 heavy atoms from 20 to 70

[edit] References

^ 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)
^ 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.
^ 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)