Lipinski’s Rules

Lipinski’s Rule of Five

Christopher Lipinski’s rule of five analysis helped to raise awareness in scientific community about molecular properties that make molecules more or less drug-likeness. The rules of thumb were quickly adopted as it aided to apply absorption, distribution, metabolism and excretion (ADME) considerations early in preclinical developments and also could help to avoid preclinical and clinical failure.

Lipinski’ rule extension

In attempt to improve the predictions of drug likeness, the rules lead to many extensions and those are given below point-wise

• Partition coefficient log P  ranged from  -0.4 to +5.6
• Molar refractivity ranged from 40 to 130
• Molecular weight ranged from 180 to 500
• Number of atoms ranged from 20 to 70 (H-bond acceptors and H-bond donors)
• Polar surface area no greater than 140 Ų

In addition to that the 500 molecular weight cut-off has been uncertain. Polar surface area and the number of rotable bonds has been found to better discriminate between compounds that are orally active and those that are not for a large data set of compounds in the rat. In particular, compounds which meet only the 2 criteria of:

• 10 or fewer rotatable bonds
• Polar surface area equal to or less than 140 Å² are predicted to have good oral bio-availability.

Finally Lipniski’s fifth rule effectively states that the first four rules do not apply to any molecule if that is recognizing by an active transport system, when considering “druggable chemical entities”.