6.1. Definitions
6.1.1. Drug-likeness
Drug-likeness can be defined as a complex balance of various molecular properties, which determine whether particular molecule is drug or not. These properties influence the behavior of molecule in an organism, including characteristics such as transport, affinity to proteins, reactivity, toxicity, metabolic stability and many others. A large number of definitions for drug-likeness exist: You can choose among several definitions (Ghose, Lee, Walters & Murcko, Oprea, ...) by selecting the specific filter preset.
6.1.2. Orally administered drugs
Most drugs are developed for oral administration to ensure high compliance and acceptance. These drugs have to cross membrane barriers of the gastro-intestinal tract to get bio-available and hence, take effect. Only hydrophobic, relatively small ligands are able to diffuse across the membranes. Also, a too large number of H-bond donors and H-bond acceptors may prevent the molecule from diffusion.
6.1.3. Lead-likeness
Rational drug design is based on the research for the lead structure. Lead structures are ligands that typically exhibit suboptimal target binding affinity. Leads that are to be taken in consideration for further drug development are characterized by the following properties:
- chemical features capable of optimization and development by combinatorial and medicinal chemistry
- good ADME properties
- no reactive/toxic substructures and
- favorable patent situation
Thus, lead structures are the starting point for medicinal chemistry research. The definition of leads requires at least one marketed drug based on this particular lead structure.
In contrast to drugs, leads should be characterized by a lower molecular weight and a lower logP.
6.1.4. CNS drugs
Drugs with CNS (Central Nervous System) activity have features and properties that enable them to cross the BBB (Blood-Brain Barrier). CNS activity is believed to be a complex function of physical/chemical properties of molecules such as size, lipophilicity, hydrogen-bonding potential, charge and conformation. CNS activity can be enhanced by higher lipophilicity, by designing prodrugs or by using active or passive transport systems. In general, charged ligands are not able to cross the BBB.