Date of Graduation

Spring 2017

Document Type

Honors Research Project

Degree Name

Bachelor of Science

Major

Chemistry - Biochemistry

Research Sponsor

Dr. Thomas Leeper

First Reader

Dr. Wiley Youngs

Second Reader

Dr. Claire Tessier

Abstract

Fragment-based drug design (FBDD) is a method of pharmaceutical research involving characterization of small “fragment” molecule interactions with a target protein. These fragments are optimized with the addition of a nucleophilic “warhead” moiety. Several novel fragment-warhead adducts have been synthesized in house by group member Ram Khattri Ph.D. The experiment investigates reactivity of these adducts with glutaredoxin protein (Grx) orthologs from Homo sapiens, Pseudomonas aeruginosa and Brucella melitensis. Three novel fragment-warhead adducts have been identified to cause weakly bacteriostatic and bacteriocidal effects, most with minimum inhibitory concentration values near 1.28 mg/mL. Discussed herein are molecular effects of these fragment-warhead compounds on Grx, such as their association in inducing Grx oligomerization. Further investigation of the fragment-warhead adduct coumarin acrylamide was performed due to its fluorescent properties. Use of Grx as a druggable candidate for development of a putative antibiotic has been a relatively untapped target until recently. These results may help further characterize Grx, and its ability to mediate bacterial survivability, to aid in the fight against multi-drug resistant and opportunistic bacterial infections such as pneumonia and brucellosis.

Included in

Biochemistry Commons

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