Lipinski's rule of five

Overview

Lipinski's Rule of Five is a set of guidelines used to evaluate the druglikeness of a chemical compound. It predicts the likelihood of a compound being an orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997 and is widely used in medicinal chemistry and pharmacology.

The Rule of Five

The rule is based on the observation that most orally active drugs have certain physicochemical properties. According to Lipinski's Rule of Five, a compound is more likely to be orally active if it meets the following criteria:

• The compound has no more than 5 hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds).
• The compound has no more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms).
• The molecular weight of the compound is less than 500 daltons.
• The compound has a log P (octanol-water partition coefficient) that does not exceed 5.

These criteria are not strict rules but rather guidelines that help in the design and evaluation of potential drug candidates.

Importance in Drug Discovery

Lipinski's Rule of Five is crucial in the early stages of drug discovery and development. It helps researchers identify compounds with favorable pharmacokinetic properties, such as absorption, distribution, metabolism, and excretion (ADME). Compounds that violate more than one of these rules are less likely to be orally active.

Limitations

While Lipinski's Rule of Five is a valuable tool, it has limitations. It does not account for all factors influencing drug absorption and bioavailability, such as P-glycoprotein efflux and metabolic stability. Additionally, some drugs that violate the rule are still effective, such as antibiotics, antifungals, and natural products.

Example: Omeprazole

Omeprazole, a proton pump inhibitor, is an example of a drug that follows Lipinski's Rule of Five.

An example of a drug that adheres to Lipinski's Rule of Five is omeprazole, a widely used proton pump inhibitor for treating gastroesophageal reflux disease (GERD). Omeprazole has a molecular weight of 345.42 daltons, 1 hydrogen bond donor, 4 hydrogen bond acceptors, and a log P of 3.3, making it compliant with the rule.

Related Pages

• Drug discovery
• Pharmacokinetics
• Medicinal chemistry
• Christopher A. Lipinski