David M. Ferguson, PhD

Professor, Department of Medicinal Chemistry

David M. Ferguson

Contact Info

Ferguson@umn.edu

Office Phone 612-626-2601

Fax 612-624-0139

Office Address:
8-113 Weaver-Densford Hall
308 Harvard Street SE
Minneapolis, MN 55455

Mailing Address:
8-113 Weaver-Densford Hall
516 Delaware Street SE
Minneapolis, MN 55455

University of California (Pharmaceutical Chemistry), 1991

PhD, University of South Florida (Chemistry), 1989

Bucknell University (Chemistry), 1983

Summary

David M. Ferguson is a Professor of Medicinal Chemistry, a Fellow of the Supercomputing Institute for Digital Simulation and Advanced Computation, an Associate Director of the Center for Drug Design, and a graduate faculty member of several interdisciplinary programs across the University.

Awards & Recognition

  • Pharmacy Teacher of the Year University of Minnesota 2001, 2002, 2008, 2009, 2010
  • President's Distinguished Faculty Mentor University of Minnesota 1999/01
  • James A. Shannon Directors Award National Institutes of Health 1996/97
  • Advisor, Merck Research Scholar Program AACP 1996/97
  • Pharmacy Teacher of the Year University of Minnesota 1996/97

Professional Associations

Fellow, Minnesota Supercomputing Institute for Digital Simulation and Advanced Computation

Research

Research Summary/Interests

Research is the foundation to scholarship. Research in my lab is primarily focused on the application of chemistry to solving problems related to biomolecular structure, function, and activity, especially as it relates to drug design and discovery.  More precisely, we apply chemical synthesis, biological screening, and structural biology to understand the basis to molecular recognition and the physical forces that drive function.

For example, our work on opioid recognition defined the first structural models by which highly selective agonists and antagonists could be rationally designed.  

In the field of cancer and topoisomerase function, we designed characterized DNA binding agents that selectively inhibited topoisomerase II by threading DNA duplex and quadraplex structures thereby blocking strand cleavage. These catalytic inhibitors were further shown to avoid formation of linear DNA fragments following treatment reducing the toxic effects commonly associated with topoisomerase poisons.  Using focused library synthesis and flavivirus screening, we discovered the first non-nucleoside inhibitors or the West Nile virus.  These compounds have shown further versatility in other emerging tropical diseases and have the added advantage of being simple and cost effective to produce.

Our most recent efforts in fighting cancer have focused on immunostimulants targeting TLR7 and TLR8.  Our work has not only defined the selectivity elements leading to high affinity binding to TLR7/8 but has shown some ligands may activate an alternative pathway in the production of specific cytokines, such as IL-1b and IL-12, required to boost antigen specific cellular responses of the immune system.  More details of this work and more can be found at my website and in my published work.

Publications

  • Ferguson,D. M.; Jacobson, B. A.; Jay-Dixon, J.; Patel, M. R.; Kratzke, R. A.; Raza, A. Targeting Topoisomerase II Activity in NSCLC with 9-Aminoacridine Derivatives. Anticancer Res. 10, 5211-7, 2015.
  • Teitelbaum, A. M.; Gallardo, J. L.; Bedi, J.; Giri, R.; Benoit, A. R.; Olin, M. R.; Morizio, K. M.; Ohlfest, J. R.; Remmel, R. P.; Ferguson, D. M. 9-Amino acridine pharmacokinetics, brain distribution, and in vitro/in vivo efficacy against malignant glioma. Cancer Chemother. Pharmacol. 2012, 69, 1519-1527.
  • Shi, C.; Xiong, Z.; Chittepu, P.; Aldrich, C. C.; Ohlfest, J. R.; Ferguson, D. M. Discovery of imidazoquinolines with toll-like receptor 7/8 independent cytokine induction. ACS Med. Chem. Lett. 2012, 3, 501-504.
  • Raza, A.; Jacobson, B. A.; Benoit, A.; Patel, M. R.; Jay-Dixon, J.; Hiasa, H.; Ferguson, D. M.; Kratzke, R. A. Novel acridine-based agents with topoisomerase ii inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis. Invest. New Drugs 2012, 30, 1443-1448.
  • Giri, R.; Goodell, J. R.; Xing, C.; Benoit, A.; Kaur, H.; Hiasa, H.; Ferguson, D. M. Synthesis and cancer cell cytotoxicity of substituted xanthenes. Bioorg. Med. Chem. , 2010, 18,1456-63.
  • Oppegard, L. M.; Ougolkov, A. V.; Luchini, D. N.; Schoon, R. A.; Goodell, J. R.; Kaur, H.; Billadeau, D. D.; Ferguson, D. M.; Hiasa, H. Novel acridine-based compounds that exhibit an anti-pancreatic cancer activity are catalytic inhibitors of human topoisomerase II. Eur J Pharmacol. 2009, 602, 223-9.
  • Gálvez-Peralta, M.; Hackbarth, J. S.; Flatten, K. S.; Kaufmann, S. H.; Hiasa, H.; Xing, C.; Ferguson, D. M. On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents. Bioorg. Med. Chem. Lett. 2009, 9, 4459-62.
  • Labello, N. P.; Neres, J. Bennett, E. M.; Ferguson, D. M.; Aldrich, C. C. Quantitative Three-Dimensional Structure Linear Interaction Energy Model of 5’-O-[N-(Salicyl)sulfamoyl]adenosine and the Aryl Acid Adenylating Enzyme MbtA. J. Med. Chem. 2008, 51, 7154–7160.
  • Goodell, J. R.; Ougolkov, A. V.; Hiasa, H.; Kaur, H.; Remmel, R.; Billadeau, D. D.; Ferguson, D. M. Acridine-Based Agents with Topoisomerase II Activity Inhibit Pancreatic Cancer Cell Proliferation and Induce Apoptosis. J. Med. Chem. 2008, 51, 179-82.
  • Kane, B. E.; Mc Curdy, C. R.; Ferguson, D. M. Toward a Structure-Based Model of Salvinorin A Recognition of the K-Opioid Receptor. J. Med. Chem. 2008, 51, 1824-30.
  • Kane, B. E.; Grant, M. K. O.; El-Fakahany, E.; Ferguson, D. M. Synthesis and evaluation of xanomeline analogs—Probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor. Bioorg. Med. Chem. 2008, 16, 1376-92.
  • Singh, N.; Cheve, G.; Ferguson, D. M.; McCurdy, C. R. A Combined Ligand-Based and Target-Based Drug Design Approach for G-Protein Coupled Receptors: Application to Salvinorin A, a Selective kappa Opioid Receptor Agonist. J. Comput. Aided Mol. Des. 2006, 20, 471-93.
  • Goodell, J. R.; Madhok, A. A.; Hiasa, H.; Ferguson, D. M. Synthesis and Evaluation of Acridine- and Acridone-Based AntiHerpes Agents with Topoisomerase Activity. Bioorg. Med. Chem. 2006, 14, 5467-80.
  • Kane, B., E.; Nieto, M. J.; McCurdy, C., R.; Ferguson, D. M. A Unique Binding Epitope for Salvinorin A, a Non-Nitrogenous kappa-Opioid Receptor Agonist. FEBS J. 2006, 273, 1966-74.
  • Goodell, J. R.; Puig-Basagoiti, F.; Forshey, B. M.; Shi, P.-Y.; Ferguson, D. M., Identification of Compounds with Anti-West Nile Virus Activity. J. Med. Chem. 2006, 49, 2127-37.
  • Puig-Basagoiti, F.; Tildner, M.; Forshey, B. M.;Philpott, S. M.; Espina, N. G.; Wentworth, D. E.; Goebel, S. J.; Masters, P. S.; Falgout, B.; Ren, P.; Ferguson, D. M.; Shi, P.-Y., Triaryl Pyrazoline Compound Inhibits Flavivirus RNA Replication. Antimicrob. Agents Chemother. 2006, 50, 1320-9i,
  • Goodell, J.R.; Svensson, B.; Ferguson, D.M. Spectrophotometric Determination and Computational Evaluation of the Rates of Hydrolysis of 9-Amino Substituted Acridines. J. Chem. Inf. Model. 2006, 46, 876-83.
  • Kane, B.; Svensson, B.; Ferguson, D. M. Molecular Recognition of Opioid Receptor Ligands. AAPS J. 2006, 8, E126-137.
  • Puig-Basagoiti, F.; Deas, T. S.; Ren, P.; Tilgner, M.; Ferguson, D. M. Shi,* P.-Y. High-throughput assays using luciferase-expressing replicon, virus-like particle, and full-length virus for West Nile virus drug discovery. Antimicrob. Agents Chemother. 2005, 49, 4980-4988.
  • Park, S.; Seetharaman, M.; Ogdie, A.; Ferguson, D. M.; Tretyakova, N. 3 '-Exonuclease resistance of DNA oligodeoxynucleotides containing O-6-[4-oxo-4-(3-pyridyl)butyl]guanine. Nucleic Acids Res. 2003, 31, 1984-94.
  • McFadyen, I.; Metzger, T.; Subramanian, G.; Poda G.; Jorvig E.; Ferguson, D. M. Molecular modeling of opioid receptor-ligand complexes. Prog. Med. Chem. 2002, 40, 107-135.
  • Mo, Y.; Subramanian, G.; Gao. J.; Ferguson, D. M. Cation- Interactions: An Energy Decomposition Analysis and Its Implication in -Opioid Receptor-Ligand Binding. J. Am. Chem. Soc. 2002, 124, 4832-4837.
  • McFadyen, I. J.; Metzger, T. G.; Paterlini, M. G.; Ferguson, D. M. Exploring the unique pharmacology of a novel opioid receptor, ZFOR1, using molecular modeling and the message-address concept. Protein Eng. 2001, 14, 953-60.
  • Sharma, S. K.; Jones, R. M.; Metzger, T. G.; Ferguson, D. M.; Portoghese, P. S. Transformation of a kappa-opioid receptor antagonist to a kappa-agonist by transfer of a guanidinium group from the 5 '- to 6 '-position of naltrindole. J. Med. Chem. 2001, 44, 2073-2079.
  • Le Bourdonnec, B.; El Kouhen, R.; Poda, G.; Law, P. Y.; Loh, H. H.; Ferguson, D. M.; Portoghese, P. S. Covalently induced activation of the delta opioid receptor by a fluorogenic affinity label, 7 '-(phthalaldehyde-carboxamido)naltrindole (PNTI). J. Med. Chem. 2001, 44, 1017-1020.
  • Metzger, T. G.; Paterlini, M. G.; Ferguson, D. M.; Portoghese, P. S. Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: Exploring the 'address' recognition locus. J. Med. Chem. 2001, 44, 857-862.
  • Podlogar, B.; Ferguson, D. M. QSAR and CoMFA: A perspective on the practical application to drug discovery. Drug Des. Discovery 2000, 17, 4-12.
  • Subramanian, G.; Ferguson, D. M. Conformational landscape of selective mu-opioid agonists in gas phase and in aqueous solution: The fentanyl series. Drug Des. Discovery 2000, 17, 55-67.
  • Podlogar, B.; Poda, G. I.; Demeter, D. A.; Zhang, S. P.; Carson, J. R.; Neilson, L. A.; Reitz, A. B. Ferguson, D. M. Synthesis and evaluation of 4-(N,N-diarylamino)piperidines with high selectivity to the delta-opioid receptor:A combined 3D-QSAR and ligand docking study. Drug Des. Discovery 2000, 17, 34-50.
  • Ferguson, D. M.; Kramer, S.; Metzger, T. G.; Law, P. Y.; Portoghese, P. S. Isosteric replacement of acidic with neutral residues in extracellular loop-2 of the kappa-opioid receptor does not affect dynorphin A(1-13) affinity and function. J. Med. Chem. 2000, 43, 1251-2.
  • Subramanian, G.; Paterlini, M. G.; Portoghese, P. S.; Ferguson, D. M. Molecular docking reveals a novel binding site for fentanyl at the mu-opioid receptor. J. Med. Chem. 2000, 43, 381-91.
  • Stevens, W.C.; Jones, R. M.; Subramanian, G.; Metger, T. G.; Ferguson, D. M.; Portoghese, P. S. Potent and selective indolomorphinan antagonists of the kappa-opioid receptor. J. Med. Chem. 2000, 43, 2759-69.
  • Paterlini, M.G.; Avitabile, F.; Ostrowski, B.G.; Ferguson, D. M.; Portoghese, P. S. Stereochemical requirements for receptor recognition of the mu-opioid peptide endomorphin-1. Biophysical J. 2000, 78, 590-599.
  • Venkateswarlu, D.; Ferguson, D. M. Effects of C2'-Substitution on Arabinonucleic Acid Structure and Conformation. J. Am. Chem. Soc. 1999, 121, 5609-10.
  • Venkateswarlu, D.; Lind, K.; Mohan, V.; Manoharan, M.; Ferguson, D. M. Structural Properties of DNA:RNA Duplexes Containing 2’-O-Methyl and 2’-S-Methyl Substitutions: A Molecular Dynamics Investigation. Nucleic Acids Res. 1999, 27, 2189-95.
  • Subramanian, G.; Paterlini, M. G.; Larson, D.; Portoghese, P. S.; Ferguson, D. M. Conformational Analysis and Automated Receptor Docking of Selective Arylacetamide-Based kappa-Opioid Agonists. J. Med. Chem. 1998, 41, 4777-89.
  • Podlogar, B. P.; Paterlini, M. G.; Ferguson, D. M.; Leo, G. C.; Demeter, D. A.; Brown, F. K.; Reitz, A. Conformational Analysis of the Endogenous mu-Opioid Agonist Endomorphin-1 using NMR Spectroscopy and Molecular Modeling. FEBS Lett. 1998, 439, 13-20.
  • Lind, K. E.; Mohan, V.; Manoharan, M.; Ferguson, D. M. Structural Characteristics of 1'-O-(2-methoxyethyl)-Modified Nucleic Acids from Molecular Dynamics Simulations. Nucleic Acids Res. 1998, 26, 3694-99.
  • Paterlini, M. G.; Ferguson, D. M. Constant Temperature Simulations using the Langevin Equation with Velocity Verlet Integration. Chemical Phys. 1998, 236, 243-52.
  • Paterlini, M. G.; Portoghese, P. S.; Ferguson, D. M. Molecular Simulation of Dynorphin A Binding to Extracellular Loop 2 of the kappa-Opioid Receptor: A Model for Receptor Activation. J. Med. Chem.1997, 40, 3254-62.
  • Marsh, A.; Ferguson, D. M. Knowledge-Based Modeling of a Bacterial Dichloromethane Dehalogenase. Proteins: Struct. Func. Gen. 1997, 28, 217-226.
  • Paterlini, M. G.; Metzger, T.; Portoghese, P. S.; Ferguson, D. M. Identification of Helical Packing Motifs Common to Bacteriorhodopsin and G-Protein Coupled Receptors. J. Mol. Mod. 1997, 3, 70-77.
  • Metzger, T.; Glauser, W.; Ferguson, D. M. A Computational Analysis of Interaction Energies In Methane and Neopentane Dimer Systems. J. Comput. Chem. 1997, 18, 70-9.
  • Metzger, T.; Paterlini, M. G.; Portoghese, P. S.; Ferguson, D. M. Application of Message-Address Concept to the Docking of Naltrexone and Selective Naltrexone-Derived Opioid Antagonists into Opioid Receptor Models. Neurochemical Res. 1996, 21, 1287-94.
  • Metzger, T.; Paterlini, M. G.; Portoghese, P. S.; Ferguson, D. M. An Analysis of the Conserved Residues Between Halobacterial Retinal Proteins and G-Protein Coupled Receptors: Implications for GPCR Modeling. J. Chem. Inf. Comp. Sci. 1996, 36, 857-61.
  • Metzger, T.; Ferguson, D. M. On the Role of Extracellular Loops of Opioid Receptors in Conferring Ligand Selectivity. FEBS Lett. 1995, 375, 1-4.
  • Chow, K.; Ferguson, D. M. Isothermal Isobaric Molecular Dynamics Simulations with Monte Carlo Volume Sampling. Comp. Phys. Com. 1995, 91, 283-9.
  • Cornell, W.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, K. M.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J. W.; Kollman, P. A. A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules, J. Am. Chem. Soc. 1995, 117, 5179-97.
  • Pearlman, D. A.; Case, D. A.; Caldwell, J. W.; Ross, W. S.; Cheatham, T., III; Debolt, S.; Ferguson, D. M.; Siebel, G.; Kollman, P. A. AMBER, Comp. Phys. Comm. 1995, 91, 1-41.
  • Ferguson, D. M. Parameterization and Evaluation of a Flexible Water Model. J. Comput. Chem. 1995, 16, 501-11.
  • Troyer, J.; Cohen, F.; Ferguson, D. M. Langevin Dynamics of Simplified Protein Models, in Proceedings of the First Electronic Computational Chemistry Conference, Ed. by S. M. Bachrach, D. Boyd, S. K. Gray, W. Hase, and H. S. Rzepa, ARInternet, 1995.
  • Ferguson, D. M.; Marsh, A.; Metzger, T.; Garrett, D. G.; Kastella, K. Conformational Searches for the Global Minimum of Protein Models. J. Glob. Opt. 1994, 4, 209-227.
  • Ferguson, D. M. On the Use of Acceptance Ratio Methods in Free Energy Calculations. J. Chem. Phys. 1993, 99, 10086-7.
  • Garrett, D. G.; Kastella, K.; Ferguson, D. M. New Results on Protein Folding from Simulated Annealing. J. Am. Chem. Soc. 1992, 114, 6555-6.
  • Veenstra, D. L.; Ferguson, D. M.; Kollman, P. A. Are Methyl Group Parameters Transferrable in Molecular Mechanics Calculations? J. Comput. Chem. 1992, 13, 971-8.
  • Swope, W. C.; Ferguson, D. M. Alternative Expressions for Energies and Forces Due to Angle Bending and Torsional Energy. J. Comput. Chem. 1992, 13, 585-94.
  • Ferguson, D. M.; Gould, I. R.; Schroeder, S.; Glauser, W.; Kollman, P. A. Application and Comparison of Ab Initio, Semiempirical, and Molecular Mechanics Calculations as Applied to Cyclic Alkanes. J. Comput. Chem.1992, 13, 525-32.
  • Ferguson, D. M.; Pearlman, D. A.; Swope, W. C.; Kollman, P. A. Free Energy Perturbation Calculations Involving Potential Function Changes. J. Comput. Chem. 1992, 13, 362-70.
  • Ferguson, D. M.; Kollman, P. A. Application of Free Energy Decomposition to Determine the Relative Stability of R and S Oligodeoxynucleotide Methylphosphonates. Antisense Res. and Dev. 1991, 1, 243-55.
  • Ferguson, D. M.; Radmer, R. J.; Kollman, P. A. Determination of the Stereoselective Binding of Peptide Inhibitors to the HN-1 Protease. J. Med. Chem. 1991, 34, 2654-9.
  • Ferguson, D. M.; Kollman, P. A. Can the Lennard-Jones 6-12 Functions Replace the 10-12 Form in Molecular Mechanics Calculations? J. Comput. Chem. 1991, 5, 620-6.
  • Ferguson, D. M.; Raber, D. J. Molecular Mechanics Calculations of Several Lanthanide Complexes; An Application of the Random Incremental Pulse Search. J. Comput. Chem. 1990, 11, 1061-71.
  • Ferguson, D. M.; Glauser, W. A.; Raber, D. J. Molecular Mechanics Conformational Analysis of Cyclononane Using the RIPS Method and Comparison with Quantum Mechanical Calculations. J. Comput. Chem. 1989, 10, 903-910.
  • Ferguson, D. M.; Raber, D. J. A New Approach to Probing Conformational Space with Molecular Mechanics: Random Incremental Pulse Search. J. Am. Chem. Soc. 1989, 111, 4371-78.
  • Brecknell, D. J.; Ferguson, D. M.; Raber, D. J. Structures of Lanthanide Shift Reagent Complexes by Molecular Mechanics Computations. J. Mol. Struct. 1985, 124, 343-351.

BOOKS/SPECIAL VOLUMES EDITED AND ORGANIZED

  • Current Topics in Medicinal Chemistry, Special Volume on Opioid Research, ed. by D. M. Ferguson, Vol. 5, 2005.
  • Monte Carlo Methods, Advances in Chemical Physics (special volume), ed. by David M. Ferguson, J. Ilja Siepmann, and Donald E. Truhlar, John Wiley and Sons, NY, 1999.
  • INVITED CHAPTERS AND JOURNAL ARTICLES
  • Nidhi Singh, Gwénaël Chevé, David M. Ferguson, Christopher R. McCurdy, “A Combined Ligand-Based and Target-Based Drug Design Approach for G-Protein Coupled Receptors: Application to Salvinorin A, A Selective Kappa Opioid Receptor Agonist”, Special Volume of G Protein-Coupled Receptors, J. Comput. Aided Mol. Design, 2006, 20, 471-93.
  • David Garrett and David M. Ferguson, "Optimal Histogram Methods", in Monte Carlo Methods: Advances in Chemical Physics, ed. by David M. Ferguson, J. Ilja Siepmann, and Donald E. Truhlar, John Wiley and Sons, NY, 1999.
  • Kenneth E. Lind, Luke D. Sherlin, Venkatraman Mohan, Richard H. Griffey, and David M. Ferguson, "Paramerization and Simulation of the Physical Properties of Phosphorothioate Nucleic Acids", ACS Symposium Series 682, ed. by N. B. Leontis and J. Santa Lucia, Jr., American Chemical Society, Washington, D.C. 1998.
  • David Garrett and David M. Ferguson in "Adaptation of Simulated Annealing to Chemical Problems", ed. by J. Kalivas, Elsevier Science, Amsterdam, 1995.

MAJOR SOFTWARE AUTHORED

  • David. A. Pearlman, David A. Case, James W. Caldwell, Wilson S. Ross, Thomas Cheatham, III, David Ferguson, George Seibel, U. Chandra Singh, Paul Weiner, and Peter Kollman, AMBER 4.1, 5.0, University of California, San Francisco (1995, 1997).
  • David M. Ferguson and Douglas J. Raber, "Random Incremental Pulse Search", Q.C.P.E. program #588 (1990).

OTHER PUBLICATIONS

  • John Troyer, Fred Cohen, and David M. Ferguson in Chemical and Engineering News, p. 34. Figure featured pictures taken from our manuscript in news article.
  • David M. Ferguson, "Rising Stars", by Mary Shafer, Health Sciences, Summer 1994.
  • Amanda Marsh and David M. Ferguson, "Supercomputing Protein Folding", MSI Research Bulletin, 9, Fall (1992).