The use of structural alerts to avoid the toxicity of pharmaceuticals

Publication date: Available online 31 August 2018Source: Toxicology ReportsAuthor(s): Carmen Limban, Diana C. Nuţă, Cornel Chiriţă, Simona Negreș, Andreea L. Arsene, Marina Goumenou, Spyros P. Karakitsios, Aristidis M. Tsatsakis, Dimosthenis A. SarigiannisAbstractIn order to identify compounds with potential toxicity problems, particular attention is paid to structural alerts, which are high chemical reactivity molecular fragments or fragments that can be transformed via bioactivation by human enzymes into fragments with high chemical reactivity. The concept has been introduced in order to reduce the likelihood that future candidate substances as pharmaceuticals will have undesirable toxic effects. A significant proportion (~78–86%) of drugs characterized by residual toxicity contain structural alerts; there is also evidence indicating the formation of active metabolites as a causal factor for the toxicity of 62–69% of these molecules. On the other hand, the pharmacological action of certain drugs depends on the formation of reactive metabolites. Detailed assessment of the potential for the formation of active metabolites is recommended to characterize a biologically active compound. Although many prescribed drugs frequently contain structural alerts and form reactive metabolites, the vast majority of these drugs are administered in low daily doses. Avoiding structural alerts has become almost a norm in new drug design. An in-depth review of the biochemical reactivit...
Source: Toxicology Reports - Category: Toxicology Source Type: research