The activity of some bacterial forms of beta-glucuronidase are associated with side effects observed with the administration of the chemotherapy drug CPT-11, a pro-drug for the topoisomerase inhibitor SN-38. In the liver, SN-38 is modified with a glucuronide group to produce less toxic SN-38G. In the large intestine, reactivation to SN-38 occurs when beta-glucuronidase cleaves the glucuronide group from SN-38G, leading to severe gastrointestinal damage and diarrhea. Recently, a new generation of inhibitors, including Z-77, has been shown to decrease the damage associated with CPT-11 dosage. These inhibitors interact with a loop found near the active site of the enzyme. This loop is necessary for inhibitor binding in bacterial beta-glucuronidase, but does not exist in the human form of the enzyme, allowing specific targeting. F365 in this loop has been shown to make direct stacking interactions with the Z-77 inhibitor. To determine the importance of this residue in the binding of Z-77, mutations of F365 to alanine, leucine, tyrosine, and tryptophan were made using ICM-Pro from Molsoft, LLC and docking studies were performed to predict the thermodynamics of inhibitor binding. Additionally, molecular changes to the Z-77 itself were created and characterized to determine the pharmacophore using this software. The results of these studies will hopefully guide future structure-based drug design.

Molecular modeling of the Z-77 inhibitor binding to the bacterial loop of <i>E. coli</i> beta-glucuronidase

251st National Meeting (2016)

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Molecular modeling of the Z-77 inhibitor binding to the bacterial loop of E. coli beta-glucuronidase