Michael Ashley Spies

Portrait
Associate Professor
Associate Professor of Biochemistry
Associate Professor of Pharmaceutical Science Experimental Therapeutics - Medicinal and Natural Products Chemistry

Contact Information

Office
Medicinal & Natural Products Chemistry, 115 S Grand Av
Iowa City, IA 52242
319-335-5645

Fax
319-335-8766

Staff Contact
319-335-8802

Research Summary

Our research group investigates the fundamental properties of protein-ligand interactions, from a physical and chemical perspective. Our primary focus is on pharmaceutically relevant enzymes. The application and development of computational chemistry often plays a central role in addressing research questions centering on the discovery and design of novel ligands to validated drug targets. Computational insights are bolstered by in vitro and in vivo assays. Ongoing projects include: i) development of parallelized in silico docking using high performance computing (HPC) on the University of Iowa's Helium cluster, ii) use of steered molecular dynamics to perform highly accurate and precise free energy calculations to accurately rank order drug leads to a number of antimicrobial and antineoplastic targets, iii) use of hybrid QM/MM electronic structure methods to understand remote allosteric modulation of enzyme catalytic power.

Publications

Chhesda, P., Spies, M. & Spies, M. A. (In Press). Small-molecule Effectors of DNA Repair Proteins: Applications for Development of Cancer Therapeutics and Research. In Burger's Medicinal Chemistry, Drug Discovery, and Development. (8th Edition) Wiley.

Witkin, K., Vance, N. R., Caldwell, C., Li, Q., Yu, L. & Spies, M. A. (2019). An atomistic understanding of allosteric inhibition of glutamate racemase: A dampening of native activation dynamics. ChemMedChem.

Vance, N. R., Witkin, K. R., Rooney, P. W., Li, Y., Pope, M. & Spies, M. A. (2018). Elucidating the Catalytic Power of Glutamate Racemace by Investigating a Series of Covalent Inhibitors. ChemMedChem, 13(23), 2514-2521. PMID: 30264520.

Li, Q., Gakhar, L. & Spies, M. A. (2018). Determinants of human glucokinase activation and implications for small molecule allosteric control. Biochim Biophys Acta, 1862(9), 1902-1912. PMID: 29885360.

Li, Q., Folly da Silva Constantino, L. & Spies, M. A. (2018). Integrating Experimental and In Silico HTS in the Discovery of Inhibitors of Protein-Nucleic Acid Interactions. Methods Enzymol., 601, 243-273. PMID: 29523234.

Vance, N. R., Gakhar, L. & Spies, M. A. (2017). Allosteric Tuning of Caspase-7: A Fragment-Based Drug Discovery Approach. Angewandte Chemie (International ed. in English), 56(46), 14443-14447. PMID: 28940929.

Hengel, S. R., Spies, M. A. & Spies, M. (2017). Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy. Cell Chem. Bio., 24(9), 1101-1119. DOI: 10.1016/j.chembiol.2017.08.027.

Hengel, S. R., Malacaria, E., da Folly Silva Constantino, L., Bain, F. E., Diaz, A., Koch, B. G., Yu, L., Wu, M., Pichierri, P., Spies, M. A. & Spies, M. (2016). Small-molecule inhibitors identify the RAD52-ssDNA interaction as critical for recovery from replication stress and for survival of BRCA2 deficient cells. eLife, 5. PMID: 27434671.

Marsden, A. E., King, J. M., Spies, M. A., Kim, O. K. & Yahr, T. L. (2015). Inhibition of Pseudomonas aeruginosa ExsA DNA-Binding Activity by N-Hydroxybenzimidazoles. Antimicrobial agents and chemotherapy, 60(2), 766-76. PMID: 26574012.

Dean, S. F., Whalen, K. L. & Spies, M. A. (2015). Biosynthesis of a Novel Glutamate Racemase Containing a Site-Specific 7-Hydroxycoumarin Amino Acid: Enzyme-Ligand Promiscuity Revealed at the Atomistic Level. ACS central science, 1(7), 364-373. PMID: 26539562.

Spies, M. A. (2013). Nexus Between Protein–Ligand Affinity Rank-Ordering, Biophysical Approaches, and Drug Discovery. ACS Medicinal Chemistry Letters, 4(10), 895-897. DOI: 10.1021/ml4003502.

Subramanyam, S., Jones, W. T., Spies, M. & Spies, M. A. (2013). Contributions of the RAD51 N-terminal domain to BRCA2-RAD51 interaction. Nucleic acids research, 41(19), 9020-32. PMID: 23935068.

Whalen, K. L., Chau, A. C. & Spies, M. A. (2013). In silico optimization of a fragment-based hit yields biologically active, high-efficiency inhibitors for glutamate racemase. ChemMedChem, 8(10), 1681-9. PMID: 23929705.

Whalen, K. L., Spies, M. A. (2013). Flooding enzymes: quantifying the contributions of interstitial water and cavity shape to ligand binding using extended linear response free energy calculations. Journal of chemical information and modeling, 53(9), 2349-59. PMID: 24111836.

Whalen, K. L., Chang, K. & Spies, M. (2011). Hybrid Steered Molecular Dynamics-Docking: an efficient solution to the problem of ranking inhibitor affinities against a flexible drug target. Molecular Informatics, 30(5), 459-471.

Whalen, K. L., Pankow, K. L., Blanke, S. R. & Spies, M. (2011). Nature of Allosteric Inhibition in Glutamate Racemase: Discovery and Characterization of a Cryptic Inhibitory Pocket using Atomistic MD Simulations and pKa Calculations. J. Phys. Chem. B., 115(13), 3416-24.

Whalen, K. L., Pankow, K. L., Blanke, S. R. & Spies, M. (2010). Exploiting Enzyme Plasticity in Virtual Screening: High Efficiency Inhibitors of Glutamate Racemase. ACS Med. Chem. Lett., 1(1), 9-13.

Lin, L. J., Yoshinaga, A., Lin, Y., Guzman, C., Chen, Y. H., Mei, S., Lagunas, A. M., Koike, S., Iwai, S., Spies, M., Nair, S. K., Mackie, R. I., Ishino, Y. & Cann, I. K. (2010). Molecular analyses of an unusual translesion DNA polymerase from Methanosarcina acetivorans C2A. J. Mol. Biol., 397(1), 13-30.

Dodd, D., Kocherginskaya, S. A., Spies, M. A., Berry, K. E., Abbas, C. E., Mackie, R. I. & Cann, I. (2009). Biochemical Analysis of a Beta-D-xylosidase and a Bifunctional 1 Xylanase-Ferulic Acid Esterase from a Xylanolytic Gene Cluster in Prevotella ruminicola 23.

Spies, M. A., Reece, J. G., Dodd, D., Pankow, K. L., Blanke, S. R. & Baudry, J. (2009). Determinants of Catalytic Power and Ligand Binding in Glutamate Racemase. J. Am. Chem. Soc., 131(14), 5274-5284.

Bae, B., Ohene-Adjei, S., Kocherginskaya, S., Mackie, R. I., Spies, M. A., Cann, I. & Nair, S. K. (2008). Molecular Bases for the Promiscuity and Specificity of Ligand Recognition by the Carbohydrate Binding Modules from Thermoanaerobacterium polysaccharolyticum manA. J. Biol. Chem., 283(18), 12415-12425.

Cann, I., Dodd, D., Nair, S. K., Mackie, R. I. & Spies, M. A. (2007). Bacterial genome mining to advance enzymology for plant cell wall degradation. Invited Review. The 7th International Symposium on the Nutrition of Herbivores (ISNH-7), Beijing, China.

Dodd, D., Reese, J. G., Louer, C. R., Ballard, J. D. & Spies, M. A. (2007). Functional Comparison of the Two Bacillus Anthracis Glutamate Racemases. J Bacteriol., 189(14), 5265-5275.

Moore, R. H., Spies, M. A., Culpepper, M. B., Murakawa, T., Hirota, S., Okajima, T., Tanizawa, K. & Mure, M. (2007). Trapping of a Dopaquinone Intermediate in the TPQ Cofactor Biogenesis in a Copper-containing Amine Oxidase from Arthrobacter globiformis. J. Am. Chem. Soc., 129(37), 11524-11534.

Spies, M. A., Toney, M. D. (2007). Intrinsic Primary and Secondary Hydrogen Kinetic Isotope Effects for Alanine Racemase from Global Analysis of Progress Curves. J. Am. Chem. Soc., 129(35), 10678-10685.

Spies, M. A., Toney, M. D. (2006). Multiple Hydrogen Transfers in Enzyme Action in Hydrogen-Transfer Reactions. Wiley-VCH Verlag GmbH, Weinheim, 3, 1139-1170.

Spies, M. A., Woodward, J. J., Watnik, M. R. & Toney, M. D. (2004). Alanine Racemase Free Energy Profiles from Global Analysis of Progress Curves. J. Am. Chem. Soc., 126, 7464-7475.

Spies, M. A., Toney, M. D. (2003). Multiple hydrogen kinetic isotope effects for enzymes catalyzing exchange with solvent: Application to alanine racemase. Biochemistry, 42, 5099-5107.

Christenson, S. D., Weiming, W., Spies, M. A., Shen, B. & Toney, M. D. (2003). Kinetic analysis of the 4-Methylideneimidazole-5-one-Containing Tyrosine Aminomutase in Enediyne Antitumor Antibiotic C-1027 Biosyntheses. Biochemistry, 42, 12708-12718.

Spies, M. A., Schowen, R. L. (2002). The trapping of a spontaneously "flipped-out" base from double helical nucleic acids by host-guest complexation with Beta-cyclodextrin: The intrinsic base-flipping rate constant for DNA and RNA. J. Am. Chem. Soc., 124, 14049-14053.

Takusagawa, F., Fujioka, M., Spies, M. A. & Schowen, R. L. (1998). S-Adenosylmethionine (AdoMet)-dependent Methyltransferases. Comprehensive Biological Catalysis, Academic Press, London, 1, 1-30.

Chen, Z., Spies, M. A., Hein, R., Zhou, X., Thomas, B. C., Richter, M. L. & Gegenheimer, P. A. (1995). A subunit interaction in chloroplast ATP synthase determined by genetic complementation between chloroplast and bacterial ATP synthase genes. J. Biol. Chem., 270(29), 17124-17132.