Lipinski’s Rule of Five, also known as Pfizer’s Rule of Five or simply the Rule of Five, is a valuable guideline in pharmaceutical research and drug development. It was developed by Christopher A. Lipinski in 1997 to assess the drug-likeness of chemical compounds, especially in terms of their suitability for oral administration in humans. This rule considers four key molecular properties that influence a compound’s pharmacokinetics but does not predict its pharmacological activity. This set of criteria assists professionals in the pharmaceutical and medicinal chemistry fields in selecting suitable drug candidates and optimizing drug design. It is a fundamental concept in drug design and development, providing a practical framework to evaluate the drug-likeness of chemical compounds. By considering factors such as molecular weight, logP, hydrogen bond donors and acceptors, and rotatable bonds, researchers and students in pharmaceutical sciences can make informed decisions about drug candidates’ suitability for oral administration. However, it is crucial to remember that these guidelines are not definitive, and further evaluation is necessary to assess a compound’s potential as a drug.
The Four Criteria of Lipinski’s Rule of Five:
1. Molecular Weight (MW) < 500 Daltons:
- Molecular weight refers to the sum of the atomic weights of all atoms in a molecule.
- Compounds with a molecular weight of less than 500 Daltons are generally considered favorable for drug development, as they tend to have better bioavailability and permeability.
2. LogP (Partition Coefficient) < 5:
- LogP represents the octanol-water partition coefficient, which measures a compound’s lipophilicity.
- A logP value not exceeding 5 indicates an appropriate balance between hydrophilicity and lipophilicity for efficient drug absorption.
3. Hydrogen Bond Donors ≤ 5:
- Hydrogen bond donors are nitrogen or oxygen atoms within the molecule that can form hydrogen bonds with other molecules.
- A drug candidate should have no more than five hydrogen bond donors, which ensures good oral bioavailability.
4. Hydrogen Bond Acceptors ≤ 10:
- Hydrogen bond acceptors are nitrogen or oxygen atoms that can accept hydrogen bonds from other molecules.
- To maintain drug-likeness, a compound should have fewer than ten hydrogen bond acceptors. *Additional Rule: Given by Verber
5. Rotatable Bonds ≤ 10 (Veber’s Rule):
- Veber’s Rule suggests that a drug candidate should have no more than ten rotatable bonds.
- A higher number of rotatable bonds can negatively impact a compound’s bioavailability and absorption.
Follow the link for finding the ADME properties of any compound http://www.swissadme.ch/index.php
It’s essential to recognize that while Lipinski’s Rule of Five serves as a valuable screening tool, it is not an absolute rule. Many successful drugs deviate from one or more of these criteria. Therefore, these guidelines should be viewed as initial filters rather than strict rules.