Electronic Theses and Dissertations

Date of Award

2013

Document Type

Dissertation

Degree Name

Ph.D. in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Randy M. Wadkins

Second Advisor

Robert J. Doerksen

Third Advisor

Daniell Mattern

Relational Format

dissertation/thesis

Abstract

Alpha/beta hydrolases (ABHs) are a superfamily of hydrolytic enzymes that process a wide variety of substrates. A subfamily of ABHs called carboxylesterases (CEs) are important enzymes that catalyze biological detoxification, hydrolysis of certain pesticides, and metabolism of many esterified drugs. The chemotherapy drug irinotecan used for treatment of colorectal cancer is metabolized to SN-38, the active drug metabolite, by two CE isozymes CES1 (localized in the liver) and CES2 (localized in the small intestines). CES2's ability to activate irinotecan at a faster rate than CES1 creates a localization of activated SN-38 in the gut epithelium, resulting in the dose limiting side effect of delayed diarrhea. Development of inhibitors for the CE subfamily of ABHs could assist in ameliorating the toxic side effects associated with some esterified prodrugs such as irinotecan, and enhance the distribution of prodrugs in vivo. Hence, our research targets CES2 for inhibitor design with the goal of amelioration of intestinal cytotoxicity associated with irinotecan chemotherapy. In this work we (i) utilized QSAR technology to design and optimize novel sulfonamide CES2 inhibitors; (ii) combined QSAR with in silico design to generate new CE inhibitor scaffolds that maintained the potency of previous CE inhibitor generations, yet had improved water solubility; and ( iii) investigated the contribution of the loop 7 in CEs to sensitizing the enzyme to inhibition by sulfonamides through docking analysis. Our QSAR model, developed using 57 sulfonamide analogs, identified several features of this class of CE inhibitor that confer their potency. Using a QSAR model, constructed using 4 classes of CE inhibitors (benzils, benzoins, isatins, and sulfonamides), as a pocket site to perform in silico design we generated several new scaffolds predicted to have good solubility and potency. This work suggests that the inner loop 7 on CE plays a role in inhibitor selectivity, and interactions with this loop should be considered in the development of selective CE inhibitors. The contributions from this work will be applicable to the design of novel ABH inhibitors, help to increase the likelihood of these drugs entering in clinical use, and ameliorate the dose-limiting side effect associated with irinotecan.

Included in

Biochemistry Commons

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