Homework Sourse10 Write and explain modified Lipinskis rule of 5 RO5 with V
10) Write and explain modified Lipinski’s rule of 5 (RO5) with Veber modification and Ghose filter.
Solution
The rule was proposed by C. A. Lipinski in 1997, based on the observation that most medication drugs are relatively small and lipophilic molecules. Lipinski\'s rule of five or Pfizer\'s rule of five or simply the Rule of five (RO5) is used to evaluate drug likeness 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. According to Lipinski’s an orally active drug has no more than one violation of the following criteria: 1. Not more than 5 hydrogen bond donors; 2. Not more than 10 hydrogen bond acceptors; 3. A molecular mass less than 500 daltons; 4. An octanol-water partition coefficient log P not greater than 5.
To improve the predictions of druglikeness, the rules have several extensions. Some of them are modified by Veber.
Partition coefficient log P in 0.4 to +5.6 range; Molar refractivity from 40 to 130; Molecular weight from 180 to 500; Number of atoms from 20 to 70 (includes H-bond donors [e.g.;OH\'s and NH\'s] and H-bond acceptors [e.g.; N\'s and O\'s]); Polar surface area no greater than 140 2
Polar surface area and the number of rotatable bonds has been found to good discriminate between compounds that are orally active.
In particular, compounds which possess 10 or fewer rotatable bonds and polar surface area equal to or less than 140 Å2 are predicted to have good oral bioavailability.
