ENR is an enzyme found in both humans and bacteria, however there are significant differences between the two organisms. This makes it an ideal target for an antibiotic, reducing the likelihood of side effects in the human cells.
Once an inhibitor has been found for ENR, potentially by screening candidate molecules, it is possible to modify the molecule to improve its specificity.
Diazaborine-class molecules were developed, and successfully inhibited ENR function. However, the boron atom was found to have toxic effects in humans. Substituting the atom reduced its inhibitory action, preventing the drug from functioning.
Additionally, resistance was found to develop easily to diazaborine, making it a less useful drug. Only a single residue mutation is necessary to prevent diazaborine from binding, making it easy to develop.
‘Decorating’ drug molecules can be a good strategy to improve a drug’s mechanism of action and specificity, but this does not always work – as demonstrated by diazaborine. Alternative methods, such as de novo design of drug compounds can be successful where a specific target is identified. This design technique is becoming more common with advanced computing technologies.