Experimental and Theoretical Investigation of the Coordination of 8-Hydroxquinoline Inhibitors to Biomimetic Zinc Complexes and Histone Deacetylase 8 (HDAC8)
Anthony M. Baudino,
Harris F. Ciaccio,
Michael J. Turski,
Xavier A. Akins,
Phoebus Sun Cao,
Elisa Morales,
Roger D. Sommer,
Adam R. Johnson,
Donald J. Wink,
Kyle A. Grice,
Kari L. Stone
Affiliations
Anthony M. Baudino
Department of Chemistry, Lewis University, One University Parkway, Romeoville, IL 60490, USA
Harris F. Ciaccio
Department of Chemistry and Biochemistry, DePaul University, 1110 West Belden Ave, Chicago, IL 60614, USA
Michael J. Turski
Department of Chemistry and Biochemistry, DePaul University, 1110 West Belden Ave, Chicago, IL 60614, USA
Xavier A. Akins
Department of Chemistry and Biochemistry, DePaul University, 1110 West Belden Ave, Chicago, IL 60614, USA
Phoebus Sun Cao
Department of Chemistry and Biochemistry, DePaul University, 1110 West Belden Ave, Chicago, IL 60614, USA
Elisa Morales
Department of Chemistry, Lewis University, One University Parkway, Romeoville, IL 60490, USA
Roger D. Sommer
Molecular Education, Technology and Research Innovation Center (METRIC), North Carolina State University, Raleigh, NC 27695, USA
Adam R. Johnson
Department of Chemistry, Harvey Mudd College, 301 Platt Blvd, Claremont, CA 91711, USA
Donald J. Wink
Department of Chemistry and Learning Sciences Research Institute, University of Illinois at Chicago, 845 W. Taylor Street, Rm 4500, Chicago, IL 60607, USA
Kyle A. Grice
Department of Chemistry and Biochemistry, DePaul University, 1110 West Belden Ave, Chicago, IL 60614, USA
Kari L. Stone
Department of Chemistry, Lewis University, One University Parkway, Romeoville, IL 60490, USA
Zinc is integral to diverse biological functions, acting catalytically, structurally, and supportively in essential enzyme cycles, despite its limited amounts in the body. Targeting zinc enzymes with potent drugs, such as Vorinostat, demonstrates the therapeutic efficacy of zinc-binding ligands, notably in cutaneous T-cell lymphoma treatments. Our study merges experimental and theoretical approaches to analyze the coordination of 8-hydroxylquinoline (8HQ) inhibitors with biomimetic zinc complexes and human histone deacetylase 8 (HDAC8), a monozinc hydrolase enzyme. Assessing 10 8HQ derivatives for structural and electronic characteristics against these models, we observe minimal inhibition efficacy, corroborated through protein–ligand docking analyses, highlighting the complexities of inhibitor–zinc enzyme interactions and suggesting intricate noncovalent interactions that are important for ligand binding to enzymes not accounted for in model zinc hydrolase mimics.
