The Biochemistry of Drug Design

Scientists develop drugs with the best of intentions, but at times they find that the drugs they create interact negatively with the body, or with the microbiome. For instance, the anti-cancer drug camptothecin (CPT-11), commonly used to treat colon cancer and, at times, brain and lung cancer, but it causes severe intestinal distress in about 40% of patients. This is from an unfavorable interaction that microbes have with the drug, wherein they reactivate CPT-11 after the liver deactivates it, leading to prolonged effects in the body. Scientists were able to find that there was an enzyme, beta-glucuronidase, removes the deactivating glucuronic acid from CPT-11 and the bacterial form of beta-glucuronidase is significantly different than the human form, making it possible to create an inhibitor for bacterial beta-glucuronidase that will not effect the human form. They found that bacterial beta-glucuronidase had a catalytic glutamic acid in a loop that was completely missing in the human form, and so, knowing structural details of this enzyme, they were able to screen for molecules that would interact with this enzyme but not with human forms. It appears that this worked! A mouse model used one of these inhibitors and reduced side-effects from CPT-11 drastically, possibly making this cancer drug a more viable candidate again.

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