Pharmacophore and toxicophore

Structural features that promote biological activity are sometimes called biophores. They are divisible into pharmacophores and toxicophores. Pharmacophores impart desirable properties on a molecule (e.g., pharmacological activity or a particular fragrance). Toxicophores are responsible for undesirable effects such as toxicity (e.g., mutagenicity and skin sensitization). The same molecule can have more than one descriptor that can act as both a pharmacophore and a toxicophore in the same or different biological systems. Examples here are the toxic side effects of anti-cancer drugs and the use of Warfarin, a commercially available rat poison, to help reduce the formation of blood clots in human heart disease. 

Wermuth (2006) discussed the terms pharmacophore and toxicophore. A pharmacophore is a concept used to account for the common molecular interaction capacities of a group of compounds towards their target receptor. It can be considered as... 

The multiphore method concepmalizes a dmg as being constmcted in a modular fashion from bioactive subunits, or biophores. Since a dmg is invariably composed of many biophores, it is a multiphore. The most important biophore within the dmg stmcture is the pharmacophore, the subset of atoms within the dmg that permits energetically favorable binding to the receptor site with the elucidation of a subsequent beneficial biological response. Other portions of the molecule determine the metabolic and toxicological properties of the dmg these are the metabophores and toxicophores, respectively. 

As a lead compound is optimized, enhancing the features of the pharmacophore in order to elicit a more energetic therapeutic interaction with the receptor is important. So too is modifying toxicophores to lessen or eliminate side effects. In addition to these pharmacodynamic and toxicodynamic considerations, pharmacokinetic considerations need to be addressed. The goal here is to modify the metabophore where possible to minimize the drug s metabolism in the liver and its rapid excretion by the kidneys, thereby giving the molecule a greater chance to exert its desired pharmacodynamic effects. 

As mentioned previously, major problems can arise if pharmacophores between primary therapeutic targets and off-targets (toxicophores) associated with ADRs are shared. In this case, teams should do a thorough SAR analysis and, based on the severity of overlap, either consider a different scaffold or switch to a different target for the same indication. 

Kaufman JJ, Koski WS, Harihan P, Crawford J, Garmer DM, Chan-Lizardo L. Prediction of toxicology and pharmacology based on model toxicophores and pharmacophores using the new TOX-MATCH-PHARM-MATCH program. IntJ Quantum Chem, Quantum Biol Symp 1983 10 375-416. 

---