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Principal Investigator: Sarah Elizabeth Champagne
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $24,651
Funding agency: National Institute of General Medical Sciences
Project Summary
The ability to access complex target molecules with sustainable methodology is imperative to the development
of novel drugs, which will be necessary to treat antimicrobial resistance and emerging infectious diseases.1 Site-
selective oxidation reactions are fundamental to the current synthetic logic towards complex scaffolds and the
decoration of these cores, which is key to the development of novel drugs.2,3 Nature can use enzymes to impart
exquisite site-selectivity in oxidations based on the three-dimensional control exerted by the active site while
bringing a substrate and oxidant together. Taking inspiration from Nature, I plan to utilize flavin-dependent
monooxygenases to site-selectively oxidize a variety of non-native arenes and heteroarenes substrates (Aim 1),
which will allow access to novel building blocks, pharmaceuticals, and natural products and their derivatives.
The sequence space of flavin-dependent monooxygenases is vast, therefore, logically picking biocatalysts that
have improved, site-selectivity, yield, or substrate scope, requires a strategy. I plan to use sequence similarity
networks, (to visualize how similar sequences are), sequence alignments, (to probe amino acid changes
proximal to active sites), three-dimensional active site analysis, (to identify key amino acids and size of active
site), and docking studies, (to understand how a substrate interacts with an active site) (Aim 2). These techniques
can be used together to explain and predict trends in substrate scope, and site-selectivity. Ultimately, these
techniques will help me to logically choose biocatalysts that have improved properties such as expanded
substrate scope, divergent site-selectivity, or improved yield to strengthen the proposed oxidative method
development.
Together these aims will develop site-selective biocatalytic oxidation methods applicable to a variety of arene
and heteroarene substrates. This research will broadly impact biocatalysis investigations by developing a high
throughput platform for nonnative substrate screening across a family of enzymes, and informing what tools are
important for rationally choosing existing biocatalysts. Finally, the proposed site-selective oxidative method will
improve the ease and efficiency of synthesis and derivatization of molecules that are important to human health.
Terms: <3-D><3-Dimensional><3D><Acceleration><Active Sites><Address><Affinity><Amino Acids><Antimicrobial Resistance><Binding><Biological><Breathing><COVID-19><CV-19><Carbol><Carbolic Acid><Chemicals><Communicable Diseases><Complex><Computational toolkit><Coronavirus Infectious Disease 2019><Data><Data Bases><Databases><Derivation><Derivation procedure><Development><Disease><Disorder><Docking><Drug resistance><Drugs><Ebola><Electronics><Emerging Communicable Diseases><Emerging Infectious Diseases><Enzyme Gene><Enzymes><Family><Flavins><Health><Human><Hydroxybenzene><Hydroxylases><Hydroxylation><Indoles><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Investigation><Left><Libraries><Logic><Mediating><Medication><Metabolic><Methodology><Methods><Mixed Function Oxidases><Mixed Function Oxygenases><Modern Man><Molecular Interaction><Monooxygenases><Natural Products><Nature><Oral><Oxidants><Oxidizing Agents><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phenols><Position><Positioning Attribute><Property><Reaction><Research><Respiratory Aspiration><Respiratory Inspiration><Route><SEQ-AN><Sequence Alignment><Sequence Analyses><Sequence Analysis><Site><Solubility><Substrate Interaction><Techniques><Visualization><aminoacid><anti-microbial resistant><biologic><catalyst><computational toolbox><computational tools><computational toolset><computer based prediction><computerized tools><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><data base><developmental><drug resistant><drug/agent><electron acceptor><electronic><electronic device><improved><inspiration><method development><naturally occurring product><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><non-Native><nonnative><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oxidation><pharmaceutical><predictive modeling><pyridine><resistance to Drug><resistance to anti-microbial><resistant to Drug><resistant to antimicrobial><scaffold><scaffolding><screening><screenings><sequencing alignment><small molecule><three dimensional><tool><trend>