Skip to Main Content


Ernesto Freire


114A Biology East
Department of Biology
Johns Hopkins University
3400 N. Charles Street
Baltimore, MD 21218-2685

Joint Appointment
Department of Biophysics and Biophysical Chemistry
Johns Hopkins Medical Institutions
Office 410 516-7743
Lab 410 516-7742
Departmental fax 410 516-5213


University Cayetano Heredia


University Cayetano Heredia


University of Virginia

Research Interests

The ultimate goal of biomedical research is to cure disease. Fundamental research in this laboratory has resulted in the development of a thermodynamic platform for drug discovery and optimization. This platform is permanently improved and simultaneously applied to the discovery and optimization of novel drugs against important diseases for which no successful therapies are available. The optimization platform is aimed at achieving extremely high binding affinity and selectivity as well as appropriate pharmacokinetics. Drug targets under investigation are:

HIV/-1 Protease Inhibitors. HIV/AIDS

Plasmepsin inhibitors. Malaria

HCV Protease inhibitors. Hepatitiis C.

Coronavirus 3CL-pro Protease Inhibitors. SARS and other viral infections.

HIV-1 gp120 inhibitors. HIV/AIDS

Chymase Inhibitors. Cardiovascular Disease.

Beta Lactamase Inhibitors. Antibiotic Resistance.

If you are interested in licensing some of our technologies or lead compounds please contact the Johns Hopkins Office of Technology Transfer at:

Representative Publications
2009 - 2011

•    Freire, E., Schön, A., Velazquez-Campoy, A. (2009) Isothermal Titration Calorimetry: General Formalism Using Binding Polynomials. Methods in Enzymology. 455, 127- 155

•    Freire, E. ITC: Affinity is not everything (2009) European Pharmaceutical Review 14, 44-47

•    Brower, E. T., Schon, A., Klein, J. C., and Freire, E. (2009) Binding Thermodynamics of the N-Terminal Peptide of the CCR5 Coreceptor to HIV-1 Envelope Glycoprotein gp120. Biochemistry 48, 779-785

•    Chunlong Ma, Alexei Polishchuk, Yuki Ohigashi, Amanda Stouffer, Arne Schön, Emma Magavern, James D. Lear, Ernesto Freire, Robert A. Lamb, William F. DeGrado, and Lawrence H. (2009) Pinto Identification of the Functional Core of the Influenza A Virus A/M2 Proton-Selective Ion Channel. Proceedings of the National Academy of Sciences 106:12283-12288

•    Regnier Thomas, Diganta Sarma,Koushi Hidaka, Usman Bacha, Ernesto Freire, Yoshio Hayashi and Yoshiaki Kiso. (2009) New Developments for the Design, Synthesis and Biological Evaluation of Potent SARS-CoV 3CLpro Inhibitors. Bioorganic & Medicinal Chemistry Letters 19, 2722-2727

•    Kassa A, Madani N, Schön A, Haim H, Finzi A, Xiang SH, Wang L, Princiotto A, Pancera M, Courter J, Smith AB 3rd, Freire E, Kwong PD, Sodroski J. (2009) Transitions to and from the CD4-bound conformation are modulated by a single-residue change in the human immunodeficiency virus type 1 gp120 inner domain. J. Virol. 2009 83, 8364-8378

•    Ernesto Freire (2009) A thermodynamic approach to the optimization of drug candidates Chem Biol Drug Design 74, 468-47

•    E. Freire, A. Schon and A. Velazquez-Campoy (2009) Isothermal Titration Calorimetry: General Formalism Using Binding Polynomials. Methods Enzymol. 455, 127-155

•    E. Freire, Y. Kawasaki, A. Velazquez-Campoy and A. Schön (2011) Characterization of Ligand Binding by Calorimetry; in Biophysical approaches for determining ligand binding to biomolecular targets: detection, measurement and modeling, Alberto Podjarny, Annick Dejaegere and Bruno Kieffer Editors, RSC Biomolecular Sciences No 22, p 275-299

•    Ruben, A. J., Kiso, Y. and Freire, E. (2010) The Plasmepsin Family as Antimalarial Drug Targets in Aspartic Acid Proteases as Therapeutic Targets, Ghosh, A. K. Ed. WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Ch. 18, 513-547

•    Yuko Kawasaki, Eduardo E. Chufan, Virginie Lafont, Koushi Hidaka, Yoshiaki Kiso, L. Mario Amzel, and Ernesto Freire (2010) How Much Binding Affinity Can be Gained by Filling a Cavity? Chem. Biol. Drug Design 75, 143-151

•    Ladbury, J. E., Klebe, G. and Freire, E. (2010) Adding calorimetric data to decision making in lead discovery: a hot tip. Nature Review Drug Discovery, 9, 23-27

•    H. S. Lee, M. Contarino, M. Umashankara, A. Schon, E. Freire, A. B. Smith III, I. Chaiken and L. S. Penn (2010) Use of the quartz crystal microbalance to monitor ligand-induced conformational rearrangements in HIV-1 envelope protein gp120. Anal. Bioanal. Chem. 396, 1143-1152

•    E.T. Brower, A. Schon and E. Freire (2010) Naturally Occurring Variability in the Envelope Glycoprotein of HIV-1 and the Development of Cell Entry Inhibitors. Biochemistry 49, 2359–2367

•    J. Barrila, S. Gabelli, U. Bacha, L. M. Amzel and E. Freire (2010) Mutation of Asn28 Disrupts the Dimerization and Enzymatic Activity of SARS 3CLpro. Biochemistry 49 4308-4317

•    T. Miura , K. Hidaka, T. Uemura, K. Kashimoto, Y. Hori, Y. Kawasaki ,A. J. Ruben, E. Freire., T. Kimura, Y. Kiso (2010) Improvement of both plasmepsin inhibitory activity and antimalarial activity by 2-aminoethylamino substitution. Bioorganic & Medicinal Chemistry Letters 20 4836–4839

•    Umashankara M, McFadden K, Zentner I, Schön A, Rajagopal S, Tuzer F, Kuriakose SA, Contarino M, Lalonde J, Freire E, Chaiken I. (2010) The Active Core in a Triazole Peptide Dual-Site Antagonist of HIV-1 gp120. ChemMedChem 5, 1871-1879

•    Judith M. LaLonde, Mark A. Elban, Joel R. Courter, Akihiro Sugawara, Takahiro Soeta, Navid Madani, Amy M. Princiotto,Young Do Kwon, Peter D. Kwong, Arne Schön, Ernesto Freire, Joseph Sodroski, Amos B. Smith III (2011) Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening. Bioorg Med Chem 19, 91-101

•    Arne Schön, Navid Madani, Amos B. Smith, III, Judith M. Lalonde and Ernesto Freire (2011) Some Binding-Related Drug Properties are Dependent on Thermodynamic Signature. Chem Biol Drug Des 2011; 77: 161–165

•    Arne Schӧn, Sonia Y. Lam and Ernesto Freire (2011) Thermodynamics-Based Drug Design: Strategies for Inhibiting Protein-Protein Interactions, Future Medicinal Chemistry 3, 1129–1137

•    Yuko Kawasaki and Ernesto Freire (2011) Finding a Better Path to Drug Selectivity, Drug Discovery Today DOI information: 10.1016/j.drudis.2011.07.010

•    Rogelio Siles, Yuko Kawasaki, Patrick Ross and Ernesto Freire (2011) Synthesis and biochemical evaluation of triazole/tetrazole-containing sulfonamides against thrombin and related serine proteases. Bioorganic & Medicinal Chemistry Letters 21 (2011), 5305-5309

Lab Members

Research Scientist:

Arne Schon

Postdoctoral Fellows:

Rogelio Siles


Victoria Kholodenko