Drug-like properties, also known as druglikeness, are a crucial concept in the pharmaceutical world. They describe the inherent characteristics of a molecule that influence its potential for successful drug development.
In 2000, Christopher A. Lipinski proposed a defining guideline for drug-likeness: molecules with acceptable ADME (absorption, distribution, metabolism, and excretion) and toxicity profiles to reach the completion of human Phase I clinical trials. (Reference: “Drug-like properties and the causes of poor solubility and poor permeability,” Journal of Pharmacological and Toxicological Methods, 44, 235–249.)
So, what do these properties mean for a medicinal chemist? They primarily encompass:
- Solubility: The ability of the molecule to dissolve in water and biological fluids.
- Permeability: The ease with which the molecule can pass through cell membranes.
- Metabolic stability: Resistance to being broken down by the body’s metabolic processes.
- Transporter effects: The interaction of the molecule with specialized transport proteins that can affect its absorption and distribution.
These properties ultimately influence a drug’s:
- Oral bioavailability: How much of the drug reaches its target site after oral administration.
- Metabolism and clearance: How quickly the body eliminates the drug.
- Toxicity: The potential for harmful side effects.
- In vitro pharmacology: The activity of the drug in cultured cells and tissues.
In 1997, Lipinski built the concept of “Lipinski’s rule of five,” a widely recognized rule of thumb for medicinal chemistry.(Adv. Drug Delivery Rev., DOI: 10.1016/S0169-409X(96)00423-1).) It states that ideal drug candidates should possess:
- No more than 5 hydrogen bond donors (N-H and O-H groups)
- No more than 10 hydrogen bond acceptors (nitrogen and oxygen atoms)
- A molecular weight less than 500 daltons
- A calculated octanol-water partition coefficient (ClogP) less than 5
Lipinski’s rule, while not without exceptions, has undeniably guided and accelerated the development of countless small-molecule drugs, making it a cornerstone of modern drug discovery.