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Eric Walters, PhD

Associate Dean of Research, Professor

D. Eric Walters, PhD, joined the College of Pharmacy Faculty Leadership Team in 2009 and was appointed Professor of Pharmaceutical Sciences in 2010. He is also Professor of Biochemistry and Molecular Biology in the Chicago Medical School. Dr. Walters received a B.S. in Pharmacy from the University of Wisconsin in 1974 and a Ph.D. in Medicinal Chemistry in 1978. Following postdoctoral studies in the Chemistry Department at Indiana University, he carried out research in the food and pharmaceutical industries for 12 years. He joined the faculty of the Chicago Medical School in 1991. He has served as Principal Senator of the University Faculty Senate and is currently the chair of the University Faculty Affairs Committee. In the Medical School, he was Course Director for the Molecular Cell Biology course for 10 years and taught in the Medical Biochemistry course. In the Graduate School, he developed and teaches two courses: Computer Applications in Biomedical Research, and The Art of Scientific Presentation. In the College of Pharmacy, he is Course Director for the Medicinal Chemistry course sequence. His research program is focused on computer modeling of proteins and computer aided drug design. He collaborates with Prof. Arun Ghosh at Purdue University on the development of HIV protease inhibitors, and participated in the discovery of darunavir (Prezista®). He also collaborates with other investigators in the study of citrate transporters, potassium channels, and amino acid transporters. He has co-authored four books and over 90 scientific papers, holds two patents, and has given over 100 research presentations and invited lectures. Dr. Walters is currently Secretary of the Medicinal Chemistry Division of the American Chemical Society.

Courses

  • Medicinal Chemistry (College of Pharmacy)
  • Pharmaceutics I (College of Pharmacy)
  • Structure - Activity Relationships (College of Pharmacy)
  • Computer Applications in Biomedical Research (School of Graduate and Postdoctoral Studies)
  • The Art of Scientific Presentation (School of Graduate and Postdoctoral Studies)

Research

My research interest is in the application of computer modeling to drug design, protein structure-function relationships, and drug-receptor interactions. Molecular mechanics, molecular dynamics, and electronic structure calculations can provide insight into events at the molecular level which are not easily studied experimentally. Current problems of interest include:

  • Application of computer-adided drug design methodology to the discovery of new anti-viral drugs. A particular interest is inhibition of the HIV protease enzyme, in collaboration with Prof. Arun Ghosh, Purdue University.
  • Mechanisms of sweet and bitter taste transduction. Interactions between sweet and bitter taste. Inhibition of bitter taste.
  • Modeling a potassium channel, in collaboration with Prof. Henry Sackin.
  • Modeling a mitochondrial citrate transport protein, in collaboration with Prof. Ron Kaplan. I have used PyMOL and LSQMAN to prepare a brief animated movie of citrate passing through this transporter. 

Recent Publications

Variation of the aryl substituent on the piperazine ring within the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold unveils potent, non-competitive inhibitors of the inflammatory caspases.  C.R. Kent, M. Bryja, H.A. Gustafson, M.Y. Kawarski, G. Lenti, E.N. Pierce, R.C. Knopp, V. Ceja, B. Pati, D.E. Walters, and C.E. Karver.  Bioorg. Med. Chem. Lett., Epub ahead of print, Oct 12, 2016.  PMID: 27777011. 

Synthesis and biological evaluation of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives.  O.A. Phillips, R. D'Silva, T.O. Bahta, L.H. Sharaf, E.E. Udo, L. Benov, and D.E. Walters.  Eur. J. Med. Chem., 106:120-131, 2015. PMID: 26536532

Antipsychotics inhibit glucose transport: determination of olanzapine binding site in Staphylococcus epidermidis glucose/H+ symporter.  P. Babkin, A.M. George Thompson, D.E. Walters, and J.-Y. Choe.  FEBS Open Bio, 5:335-340, 2015.  PMID: 25941630. 

Design and synthesis of potent macrocyclic HIV-1 protease inhibitors involving P1-P2 ligands.  A.K. Ghosh, G.E. Schilz, L.N. Rusere, H.L. Osswald, D.E. Walters, M. Amano, and H. Mitsuya.  Org. & Biomol. Chem., 12:6842-6854, 2014. PMID: 25050776.

Can Diet Soft Drinks Make You Fat?  D.E. Walters.  Medscape, http://www.medscape.com/viewarticle/810738, 2013.

Team-Based Learning Applied to a Medicinal Chemistry Course.  D.E. Walters.  Med. Principles & Practice, 22:2-3, 2013. PMID: 23006824.

 

Properties of two cataract associated mutations located in the N-terminus of Connexin 46.  J.-J. Tong, B.C.H. Sohn, A. Lam, D.E. Walters, B.M. Vertel, and L. Ebihara.  Amer. J. Physiol:  Cell Physiol., 304:C823-C832, 2013.  PMID:  23302783.

Oligomycin frames a common drug-binding site in the ATP synthase.  J. Symersky, D. Osowski, D.E. Walters, and D.M. Mueller.  Proc. Natl. Acad. Sci. USA, 109:13961-13965 (2012).  PMID: 22869738

 

Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-Derived High Affinity P2 Ligands: Structure-Activity Studies and Biological Evaluation.  A.K. Ghosh, B.D. Chapsal, A. Baldridge, M.P. Steffey, D.E. Walters, Y. Koh, M. Amano, and H. Mitsuya.  J. Med. Chem., 54:622-634 (2011).  PMID:  21194227.

 

Binding of Glutamate to the Umami Receptor.  J.J. López Cascales, S.D. Oliveira Costa, B.L. de Groot, and D.E. Walters. Biophys. Chem.152:139-144, 2010.  PMID: 20961679

Conformational changes in BAK, a pore-forming proapoptotic Bcl-2 family member, upon membrane insertion and direct evidence for the existence of BH3:BH3 contact interface in BAK homooligomers.  K.J. Oh, P. Singh, K. Lee, K. Foss, S. Lee, M. Park, S. Lee, S. Aluvila, M. Park, P. Singh, R.-S. Kim, J. Symersky, and D.E. Walters.   J. Biol. Chem.285:28924-28937, 2010.  PMCID: PMC2937919

The yeast mitochondrial citrate transport protein: molecular determinants of its substrate specificity.  S. Aluvila, R. Kotaria, J. Sun, J.A. Mayor, D.E. Walters, D.H.T. Harrison, and R.S. Kaplan.   J. Biol. Chem.285:27314-27326, 2010.  PMCID: PMC2930730

 Mitochondrial and plasma membrane citrate transporters: discovery of selective inhibitors and application to structure/function analysis.  J. Sun, S. Aluvila, R. Kotaria, J.A. Mayor, D.E. Walters, and R.S. Kaplan.  Molec. Cell. Pharmacol.2:101-110, 2010.  PMCID: PMC2913483

A conserved arginine near the filter of Kir1.1 controls Rb/K selectivity.  H. Sackin, M. Nanazashvili, H. Li, L.G. Palmer, and D.E. Walters.  Channels4:203-214, 2010.

 Probing the Effect of Transport Inhibitors on the Conformation of the Mitochondrial Citrate Transport Protein via a Site-Directed Spin Labeling Approach.  J.A. Mayor, J. Sun, R. Kotaria, D.E. Walters, K.-J. Oh, and R.S. Kaplan.   J. Bioenerg. Biomembr.42:99-109.  2010.  PMCID: PMC2867622

 Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands.  A.K. Ghosh, S. Gemma, E. Simoni, A. Baldridge, D.E. Walters, K. Ide, Y. Tojo, Y. Koh, M. Amano, and H. Mitsuya.  Bioorg. Med. Chem. Lett.20, 1241-1246.  2010.

Ion Selectivity of α-Hemolysin with β-Cyclodextrin Adapter: II. Multi-Ion Effects Studied with Grand Canonical Monte Carlo/Brownian Dynamics Simulations.  B. Egwolf, Y. Luo, D.E. Walters, and B. Roux.  J. Phys. Chem. B114, 2901-2909. 2010.  PMCID: PMC2843906

Ion Selectivity of α-Hemolysin with β-Cyclodextrin Adapter: I. Single Ion Potential of Mean Force and Diffusion Coefficient.  Y. Luo, B. Egwolf, D.E. Walters, and B. Roux.  J. Phys. Chem. B114, 952-958. 2010.  PMCID: PMC2847479

Inhibitors of the Mitochondrial Citrate Transport Protein: Validation of the Role of Substrate Binding Residues and Discovery of the First Purely Competitive Inhibitor.  S. Aluvila, J. Sun, D.H.T. Harrison, D.E. Walters, and R.S. Kaplan.  Mol. Pharmacol.  77, 26-34.  2010.  PMCID: PMC2802432

Design and evaluation of new analogs of the sweet protein brazzein.  D.E. Walters, T. Cragin, Z. Jin, J.N. Rumbley, and G. Hellekant.  Chem. Senses  34, 679-683. 2009.  PMCID: PMC2745351

An inter-subunit salt bridge near the selectivity filter stabilizes the active state of Kir1.1.  H. Sackin, M. Nanazashvili, H. Li, L.G. Palmer, and D.E. Walters.  Biophys. J.  97, 1058 - 1066, 2009.  PMCID: PMC2726312

 Molecular dynamics study of a polymeric reverse osmosis membrane.  E. Harder, D.E. Walters, Y.D. Bodnar, R.S. Faibish, and B. Roux.  J. Phys. Chem. B  113, 10177-10182, 2009.  PMCID: PMC2847479

The yeast mitochondrial citrate transport protein:  identification of the lysine residues responsible for inhibition mediated by Pyridoxal 5'-phosphate.  S. Remani, J. Sun, R. Kotaria, J.A. Mayor, J.M. Brownlee, D.H.T. Harrison, D.E. Walters, and R.S. Kaplan.  J. Bioenerg. Biomembr. 40, 577-585, 2008.  PMCID: PMC2775541

Introduction of The Chloroplast Redox Regulatory Region In the Yeast ATP Synthase Impairs Cytochrome c Oxidase.  H. Shen, D.E. Walters, and D.M. Mueller.   J. Biol. Chem. 283, 32937-32943, 2008.  PMCID: PMC2583308

Computational docking to sweet taste receptor models.   D.E. Walters.  In Sweetness and Sweeteners:  Biology, Chemistry and Psychophysics, D.K. Weerasinghe and G.E. DuBois, Eds., Oxford University Press, 2007.

External K activation of Kir1.1 depends on the pH gate.  H. Sackin, M. Nanazashvili, H. Li, L.G. Palmer, and D.E. Walters. Biophys. J. 93, L14-L16, 2007.  PMCID: PMC1896244

Identification of the substrate binding sites within the yeast mitochondrial citrate transport protein.  C. Ma, S. Remani, J. Sun, R. Kotaria, J.A. Mayor, D.E. Walters, and R.S. Kaplan.  J. Biol. Chem. 282, 17210-17220, 2007.

Moving the pH gate of the Kir1.1 inward rectifier channel.  M. Nanazashvili, H. Li, L.G. Palmer, D.E. Walters, and H. Sackin. Channels 1, e1-e8, 2007

Presence of the anti-leukemic nucleotide analog, 2-chloro-2′-deoxyadenosine-5′-monophosphate, in a promoter sequence alters DNA binding of TATA-binding protein (TBP).  W.R. Hartman, D.E. Walters, and P. Hentosh.  Arch. Biochem. Biophys. 459, 223-232, 2007.

Interactions of the sweet protein brazzein with the sweet taste receptor.  D.E. Walters and G. Hellekant.  J. Agric. Food Chem.54, 10129-10133, 2006.  PMCID: PMC2527743

The mitochondrial citrate transport protein:  Evidence for a steric interaction between glutamine 182 and leucine 120 and its relationship to the substrate translocation pathway and identification of other mechanistically essential residues.  C. Ma, S. Remani, R. Kotaria, J.A. Mayor, D.E. Walters, and R.S. Kaplan.  Biochim. Biophys. Acta  1757, 1271-1276, 2006.

Structure-Based Design of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance.  A.K. Ghosh, P.R. Sridhar, S. Leshchenko, A.K. Hussain, J. Li, A.Yu.Kovalevsky, D.E. Walters, J.E. Wedekind, V. Grum-Tokars, D. Das, Y. Koh, K. Maeda, H. Gatanaga, I.T. Weber, and H. Mitsuya. J. Med. Chem. 49, 5252-5261, 2006.

Design and synthesis of novel HIV-1 protease inhibitors incorporating oxyindoles as the P2'-ligands.  A.K. Ghosh, G. Schiltz, R.S. Perali, S. Leshchenko, S. Kay, D.E. Walters, Y. Koh, K. Maeda, and H. Mitsuya.  Bioorg. Med. Chem. Lett.  16, 1869-1873, 2006.

Improving the taste of sweeteners.  D.E. Walters.  In Optimizing Sweet Taste in Foods, W.J. Spillane, Ed., Woodhead Publishing, Cambridge, 2006,  pp. 344-348.

 Analyzing and predicting properties of sweet-tasting compounds.  D.E. Walters.  In Optimizing Sweet Taste in Foods, W.J. Spillane, Ed., Woodhead Publishing, Cambridge, 2006,  pp. 283-291.

Structure-based design: synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors.  A.K. Ghosh, L.M. Swanson,  H. Cho, S. Leshchenko, K.A. Hussain, S. Kay, D.E. Walters, Y. Koh, and H. Mitsuya,  J. Med. Chem. 48, 3576-3585, 2005.

Structural locus of the pH gate in the Kir1.1 inward rectifier channel.  H. Sackin, M. Nanazashvili, L.G. Palmer, M. Krambis, and D.E. Walters, Biophys. J. 88, 2597-2606, 2005.  PMCID: PMC1305356

The yeast mitochondrial citrate transport protein:  Characterization of transmembrane domain III residue involvement in substrate translocation.  C. Ma, R. Kotaria, J.A. Mayor, S. Remani, D.E. Walters and R.S. Kaplan, J. Biol. Chem. 280, 2331-2340, 2005.

Homology modeled structure of the yeast mitochondrial citrate transport protein.  D.E. Walters and R.S. Kaplan, Biophys. J. 87, 907-911, 2004.  PMCID: PMC1304499

2-Chloro-2'-deoxyadenosine: alteration of DNA:TATA element binding protein (TBP) interactions.  T.T. Foley, P. Hentosh, and D.E. Walters, J. Mol. Model10, 32-37, 2004.

The mitochondrial citrate transport protein:  Probing the secondary structure of transmembrane domain III, identification of residues that likely comprise a portion o f the citrate transport pathway, and development of a model for the putative TMDIII-TMDIII' interface.  C. Ma, R. Kotaria, J.A. Mayor, L.R. Eriks, A.M. Dean, D.E. Walters, and R.S. Kaplan, J. Biol. Chem.,279, 1533-1540, 2004.

Homology-based model of the extracellular domain of the taste receptor T1R3.  D.E. Walters, Pure & Appl. Chem.74, 1117-1123, 2002.

Novel cyclourethane-derived HIV protease inhibitors:  a ring-closing olefin metathesis strategy.  A.K. Ghosh, L.M. Swanson, C. Liu, K.A. Hussain, H. Cho, D.E. Walters, L. Holland, and J. Buthod, Bioorg. Med. Chem. Lett.12, 1993-1996, 2002.

Structure-based design of non-peptide HIV protease inhibitors.  A.K. Ghosh, D. Shin, L. Swanson, K. Krishnan, H. Cho, K.A. Hussain, D.E. Walters, L. Holland, and J. Buthod, Il Farmaco56, 29-32, 2001. 

Regulation of ROMK by Extracellular Cations.  H. Sackin, S. Syn, L. G. Palmer, H. Choe, and D. E. Walters, Biophys. J. 80, 683-697, 2001.

Modifying the Temporal Profile of the High-Potency Sweetener Neotame.  I. Prakash, I. E. Bishay, N. Desai, and D. E. Walters,J. Agric. Food Chem. 49, 786-789, 2001.

Models of the Transmembrane Domains of the Yeast Mitochondrial Citrate Transport Protein.  D.E. Walters and R.S. Kaplan, J. Molecular Modeling6, 587-594, 2000.

The Yeast Mitochondrial Citrate Transport Protein:  Determination of Secondary Structure and Solvent Accessibility of Transmembrane Domain IV Using Site-directed Spin Labeling.  R.S. Kaplan, J.A. Mayor, R. Kotaria, D.E. Walters, and H.S. Mchaourab, Biochemistry39, 9157-9163, 2000.

The Yeast Mitochondrial Citrate Transport Protein:  Probing the Secondary Structure of Transmembrane Domain IV and Identification of Residues that Likely Comprise a Portion of the Citrate Translocation Pathway.  R.S. Kaplan, J.A. Mayor, D. Brauer, R. Kotaria, D.E. Walters, and A.M. Dean, J. Biol. Chem.275, 12009-12016, 2000.

The Yeast Mitochondrial Citrate Transport Protein:  Probing the Roles of Cysteines, Arg181 and Arg189 in Transporter Function.  Y. Xu, D.A. Kakhniashvili, D.A. Gremse, D.O. Wood, J.A. Mayor, D.E. Walters, and R.S. Kaplan,J. Biol. Chem.275, 7117-7124, 2000.

The Active Conformations of Neotame and other High-potency Sweeteners  D.E. Walters, I. Prakash, and N. Desai, J. Med. Chem.43, 1242-1245, 2000.

Predictive Models of Protein Active Sites.  D.E. Walters, in Protein Structure Prediction:  Methods and Protocols,  D.M. Webster, Ed., Humana Press, Totowa, NJ, 2000, pp. 349-358.

Oligomeric State of Wild-type and Cysteine-less Yeast Mitochondrial Citrate Transport Proteins.  Kotaria, R., Mayor, J.A., Walters, D.E., and Kaplan, R.S.  J. Bioenerg. Biomembr. 6, 543-549, 1999.