Lipinski's rule of five

Lipinski's Rule of Five is a set of criteria used to predict the oral bioavailability of a potential drug compound in humans. It was formulated by Christopher A. Lipinski in 1997, based on the observation of existing drug molecules. The rule is often used in pharmacology and medicinal chemistry to guide the early stages of drug discovery and development. According to Lipinski's Rule of Five, a compound is more likely to have good oral bioavailability if it does not violate more than one of the following criteria:

• No more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
• No more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)
• A molecular mass less than 500 daltons
• An octanol-water partition coefficient (logP) less than 5

Background

The development of new drugs is a complex, time-consuming, and costly process. Identifying compounds with suitable pharmacokinetic properties, including oral bioavailability, is a critical step in this process. Oral bioavailability is influenced by several factors, including solubility, permeability, and stability. Lipinski's Rule of Five serves as a heuristic tool to evaluate the drug-likeness of compounds based on their physical and chemical properties, potentially reducing the time and resources spent on unsuitable candidates.

Application

Lipinski's Rule of Five is widely applied in the initial screening of chemical libraries to identify compounds with favorable drug-like properties. It is particularly useful in the field of computational chemistry, where it can be used to filter large databases of chemical compounds before synthesis and testing. However, it is important to note that the rule is not absolute; some successful drugs do not meet these criteria, and not all compounds that satisfy these criteria will be successful drugs.

Limitations

While Lipinski's Rule of Five is a valuable tool in drug discovery, it has limitations. The rule does not account for all aspects of a compound's pharmacokinetic profile, such as its metabolism, toxicity, or target specificity. Additionally, the rule is less applicable to certain types of drugs, such as biologics, which are typically larger molecules that do not adhere to these criteria.

Extensions and Modifications

Over the years, additional rules and modifications have been proposed to complement or refine Lipinski's Rule of Five. These include the Veber rules for oral bioavailability, which focus on molecular flexibility and polar surface area, and the Rule of Three for fragment-based drug discovery, which applies more stringent criteria to smaller molecules.

Conclusion

Lipinski's Rule of Five remains a fundamental guideline in medicinal chemistry for evaluating the drug-likeness of chemical compounds. While not without its limitations, it provides a useful starting point for identifying promising drug candidates with favorable oral bioavailability characteristics.