Drug-likeness

Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is. It is estimated from the molecular structure before the substance is even synthesized and tested. A druglike molecule has properties like this:

• Optimal solubility to both water and fat, because an orally administered drug has to go through the intestinal lining, carried in aqueous blood and penetrate the lipid cellular membrane to reach the inside of a cell. The model compound for the cellular membrane is octanol, so the logarithm of the octanol/water partition coefficient, known as log P_ow, is used to estimate solubility.
• Since the drug is transported in aqueous media like blood and intracellular fluid, it has to be sufficiently water-soluble. Solubility in water can be estimated from the number of hydrogen bond donors vs. alkyl sidechains in the molecule. Low water solubility translates to slow absorption and action. Too many hydrogen bond donors, on the other hand, lead to low fat solubility, so that the drug cannot penetrate the cell wall reach the inside of the cell.
• Molecular weight: the smaller, the better, because diffusion is directly affected. 80% of traded drugs have molecular weights under 450 Dalton.
• Substructures that have known pharmacological properties.

Based on this information, druglikeness indexes can be constructed. A good druglikeness index gives the green light to known, effective drugs but rejects most other known chemicals. Ideally, using a druglikeness index leads to rejecting nonviable lead compounds before they are even synthesized. One of the traditional rules of thumb is Lipinski's Rule of Five.

Also, other factors such as substructures with known toxic, mutagenic or teratogenic affect the usefulness of a designed molecule. In fact, several poisons have a good druglikeness. Natural toxins are used in pharmacological research to find out their mechanism of action, and if it could be exploited for beneficial purposes.