Bioactivation toxicophores

Williams DP, Park BK. Idiosyncratic toxicity the role of toxicophores and bioactivation. Drug Discov Today 2003 8 1044-50. 

For many of the drugs associated with hepatotoxicity, there are examples of structurally related drugs which are latent to bioactivation and toxicity because of the absence of the toxicophore or the existence of alternate metabolic pathways. For example, the hepatotoxicity associated with the use of the anti-Parkinson s agent tolcapone does not occur with the structurally related drug entacapone, despite administration at doses similar to tolcapone (200-1000 mg QD). This disparity may be explained in part by the observation that entacapone does not succumb to the bioactivation reactions of tolcapone in humans (Scheme 15.3) [35]. It is also noteworthy that tolcapone but not entacapone is a potent uncoupler of oxidative... 

Figure 15.1 Compilation of structural alerts/toxicophores known to undergo bioactivation and examples of hepatotoxic drugs containing the structural alerts.

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. 

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