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Faculty


Kathleen M. Frey

Assistant Professor, Pharmaceutical Sciences

B.S., Molecular and Cell Biology, University of Connecticut, Storrs, CTPh.D., Pharmaceutical Sciences (Medicinal Chemistry), University of Connecticut School of Pharmacy, Storrs, CTPostdoctoral Fellow, Pharmacology, Yale University School of Medicine, New Haven, CT

Description

Dr. Frey conducts research in drug design and teaches medicinal chemistry, pharmacology, toxicology, and molecular biology. Prior to joining the Pharmaceutical Sciences faculty at LIU, Dr. Frey was a Postdoctoral Fellow at Yale University School of Medicine in the department of Pharmacology. At Yale, Dr. Frey received the Ruth L. Kirschstein postdoctoral fellowship from the National Institute of Health to design less toxic anti-HIV agents with improved resistance profiles. In addition to designing antiviral agents, Dr. Frey has worked collaboratively with other scientists in Yale Chemistry and Pharmacology departments to identify novel drug targets for lung cancer and melanoma. Dr. Frey gained experience in drug design, x-ray crystallography, and computational chemistry during her graduate career at the University of Connecticut School of Pharmacy. In collaboration with multidisciplinary scientists, Dr. Frey played a major role in designing novel antibacterial agents for methicillin-resistant Staphylococcus aureus (MRSA) and Bacillus anthracis using drug-target crystal structures. Compounds discovered from her graduate projects are now under a sublicense agreement with Spero Therapeutics, LLC (Cambridge, MA). She is also trained as an x-ray crystallographer and conducts the majority of her data collection research at the National Synchrotron Light Source (NSLS) of Brookhaven National Laboratory. Dr. Frey has authored 23 peer reviewed research articles, 1 invited review, and 1 patent in the fields of medicinal chemistry, structure-based drug design, biochemistry, microbiology, and molecular pharmacology.

Specialties

Medicinal Chemistry, Molecular Pharmacology, Biochemistry, Protein X-ray Crystallography, Computational Chemistry, Drug Design

Publications

  • Frey, K.M. (2015) Structure-enhanced methods in the development of non-nucleoside inhibitors targeting HIV reverse transcriptase variants. Future Microbiol, 10: 1767-1772. http://www.ncbi.nlm.nih.gov/pubmed/26517310
  • Gray, W.T., Frey, K.M., Laskey, S.B., Mislak, A.C., Spasov, K.A., Lee, W.G., Bollini, M., Siliciano, R.F., Jorgensen, W.L., and Anderson, K.S. (2015) Non-nucleoside Inhibitors Active Against HIV Reverse Transcriptase with K101P, a Mutation that Confers High Level Rilpivirine Resistance. ACS Med Chem Lett, 6: 1075-1079. http://www.ncbi.nlm.nih.gov/pubmed/26487915
  • Lee. W., Frey, K.M., Gallardo-Macias, R., Spasov, K.A., Chan, A.H., Anderson, K.S., and Jorgensen, W.L. (2015) Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase. Biorg Med Chem Lett, 25: 4824-file://localhost/4827. http/::www.ncbi.nlm.nih.gov:pubmed:26166629
  • Sohl, C.D., Ryan, M., Luo, B., Frey, K.M., and Anderson, K.S. (2015) Illuminating the molecular mechanism of tyrosine kinase inhibitor resistance for the FGFR1 gatekeeper mutation: the Achilles’ heel of targeted therapy. ACS Chem Biol, 10: 1319-1329. http://www.ncbi.nlm.nih.gov/pubmed/25686244
  • Frey, K.M., Puleo, D.E., Spasov, K.A., Bollini, M., Jorgensen, W.L. and Anderson, K.S. (2015) Structure-based Evaluation of Non-nucleoside Inhibitors with Improved Potency and Solubility that Target HIV Reverse Transcriptase Variants. J Med Chem, 58: 2737-2745. http://www.ncbi.nlm.nih.gov/pubmed/25700160
  • Reeve, S.M., Gainza, P., Frey, K.M., Georgiev, I., Donald, B.R., and Anderson, A.C. (2015). Protein Design Algorithms Predict Viable Resistance to an Experimental Antifolate. Proc Natl Acad Sci USA, 112: 749-754. http://www.ncbi.nlm.nih.gov/pubmed/25552560
  • Lee, W., Frey, K.M., Gallardo-Macias, R., Spasov, K.A., Bollini, M., Anderson, K.S., and Jorgensen, W.L. (2014) Picomolar Inhibitors of HIV-1 Reverse
  • MRSA and Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers. ACS Med Chem Lett, 5: 1259-1262. http://www.ncbi.nlm.nih.gov/pubmed/25408842
  • Kumar, V.P., Cisneros, J.A., Frey, K.M., Castellanos-Gonzalez, A., Wang, Y., Gangjee, A., White Jr., A.C., Jorgensen, W.L., and Anderson, K.S. (2014) Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis Thymidylate Synthase-Dihydrofolate Reductase. Biorg Med Chem Lett, 4: 4158-4161. http://www.ncbi.nlm.nih.gov/pubmed/25127103
  • Mislak, A.C., Frey, K.M., Bollini, M., Jorgensen, W.L., and Anderson, K.S., (2014). A Mechanistic and Structural Investigation of Modified Derivatives of the Diaryltriazine Class of NNRTIs Targeting HIV-1 Reverse Trancriptase. Biochim Biophys Acta, 1840: 2203-2211. http://www.ncbi.nlm.nih.gov/pubmed/24726448
  • Frey, K.M., Gray, W.T., Spasov, K.A., Bollini, M., Gallardo-Macias, R., Jorgensen, W.L., and Anderson, K.S. (2014) Structure-based Evaluation of C5 Derivatives in the Catechol Diether Series Targeting HIV-1 Reverse Transcriptase. Chem Biol Drug Des, 83: 541-549 http://www.ncbi.nlm.nih.gov/pubmed/24289305.
  • Lee, W., Gallardo-Macias, R., Frey, K.M., Spasov, K.A., Bollini, M., Anderson, K.S., and Jorgensen, W.L. (2013) Picomolar Inhibitors of HIV Reverse Transcriptase Featuring Bicyclic Replacement of a Cyanovinylphenyl Group. J Am Chem Soc, 135: 16705-16713. http://www.ncbi.nlm.nih.gov/pubmed/24151856
  • Iyidogan, P., Sullivan, T.J., Chordia, M., Frey, K.M., and Anderson, K.S. (2013) Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase. ACS Med Chem Lett, 4: 1183-1188. http://www.ncbi.nlm.nih.gov/pubmed/24900627
  • Kumar, V.P., Frey, K.M., Wang, Y., Jain, H.K., Gangjee, A., and Anderson, K.S. (2013) Substituted Pyrrolo[2,3-d]pyrimidines as Cryptosporidium hominis Thymidylate Synthase Inhibitors. Biorg Med Chem Lett, 23: 5426-5428. http://www.ncbi.nlm.nih.gov/pubmed/23927969
  • Bollini, M., Frey, K.M., Cisneros, J.A., Spasov, K.A., Das, K., Bauman, J.D., Arnold, E., Anderson, K.S., and Jorgensen, W.L. (2013) Extension into the Entrance Channel of HIV-1 Reverse Transcriptase – Crystallography and Enhanced Solubility. Biorg Med Chem Lett, 23: 5209-5212. http://www.ncbi.nlm.nih.gov/pubmed/23899617
  • Frey, K.M., Bollini, M., Mislak, A.C., Cisneros, J.A., Gallardo-Macias, R., Jorgensen, W.L., and Anderson, K.S. (2012) Crystal Structures of HIV-1 Reverse Transcriptase Reveal Key Interactions for Drug Design. J Am Chem Soc, 134: 19501-19503. http://www.ncbi.nlm.nih.gov/pubmed/23163887
  • Kim, J., Wang, L., Li, Y., Becnel, K.D., Frey, K.M., Garforth, S.J., Prasad, V.R., Schinazi, R.F., Liotta, D.C., and Anderson, K.S. (2012) Pre-steady State Kinetic Analysis of Cyclobutyl Derivatives of 2'-deoxyadenosine 5'-triphosphate as Inhibitors of HIV-1 Reverse Transcriptase. Biorg Med Chem Lett, 22: 4064-4067. http://www.ncbi.nlm.nih.gov/pubmed/22595174
  • Frey, K.M., Viswanathan, K., Wright, D.L., and Anderson, A.C. (2012) Prospective Screening of Novel Antibacterial Inhibitors of Dihydrofolate Reductase for Mutational Resistance. Antimicrob Agents Chemother, 56: 3556-3562. http://www.ncbi.nlm.nih.gov/pubmed/22491688
  • Viswanathan, K., Frey, K.M., Scocchera, E.W., Martin, B.D., Swain III, P.W. Alverson, J., Priestley, N.D., Anderson, A.C., and Wright, D.L. (2012) Toward New Therapeutics for Skin and Soft Tissue Infections: Propargyl-linked Antifolates are Potent Inhibitors of Streptococcus pyognes. PLoS One, 7(2): e29434. http://www.ncbi.nlm.nih.gov/pubmed/22347365
  • Frey, K.M., Georgiev, I., Donald, B.R., and Anderson, A.C. (2010) Predicting Resistance Mutations Using Protein Design Algorithms. Proc Natl Acad Sci USA, 107: 13707-13712. http://www.ncbi.nlm.nih.gov/pubmed/20643959
  • Frey, K.M., Lombardo, M.N., Wright, D.L., and Anderson, A.C. (2010) Towards the Understanding of Resistance Mechanisms in Clinically Isolated Trimethoprim-resistant, Methicillin-resistant Staphylococcus aureus Dihydrofolate Reductase. J Struct Biol, 170: 93-97. http://www.ncbi.nlm.nih.gov/pubmed/20026215
  • Beierlein, J.M.,* Deshmukh, L.,* Frey, K.M.,* Vinogradova, O., and Anderson, A.C. (2009) The Solution Structure of Bacillus anthracis Dihydrofolate Reductase Yields Insight into the Analysis of Structure Activity Relationships for Novel Inhibitors. Biochemistry, 48: 4100-4108. http://www.ncbi.nlm.nih.gov/pubmed/19323450
  • Frey, K.M., Liu, J., Lombardo, M.N., Bolstad, D.B., Smith, A.E., Priestley, N.D., Wright, D.L., and Anderson, A.C. (2009) Crystallographic Complexes of Wild-type and Mutant MRSA DHFR Reveal an Alternate Conformation of NADPH that May be Linked to Trimethoprim Resistance. J Mol Bio, 387: 1298-1308. http://www.ncbi.nlm.nih.gov/pubmed/19249312
  • Beierlein, J.M., Frey, K.M., Bolstad, D.B., Pelphrey, P.P., Joska, T., Smith, A.E., Priestley, N.D., Wright, D.L., and Anderson, A.C. (2008) Synthetic and Crystallographic Studies of a New Inhibitor Series Targeting Bacillus anthracis Dihydrofolate Reductase. J Med Chem, 54: 7532-7540. http://www.ncbi.nlm.nih.gov/pubmed/19007108
  • Bolstad, D.B., Bolstad, E.S., Frey, K.M., Wright, D.L., and Anderson, A.C. (2008) A structure-based approach to the development of potent and selective inhibitors of dihydrofolate reductase from Cryptosporidium. J Med Chem, 51: 6839-6852. http://www.ncbi.nlm.nih.gov/pubmed/18834108

Lectures and Presentations

Frey, K.M., Liu, J., Bolstad, D.E., Lombardo, M.N., Wright, D.L., Anderson, A.C. (2008) Crystallographic Complexes of Wild---type and Mutant MRSA DHFR Reveal Interactions for Lead Deign. North Eastern Structure Symposium: X---ray Crystallography and Computational Biology. Storrs, CT, USA.

Frey, K.M., Lombardo, M.N., Wright, D.L., Anderson, A.C. (2010) Towards the Understanding of Mutational Resistance Mechanisms in MRSA DHFR. Keystone Symposia: New Directions in Small Molecule Drug Discovery. Whistler, BC, Canada.

Frey, K.M., Georgiev, I., Donald, B.R., Anderson, A.C. (2010) Predicting Resistance Mutations Using Protein Design Algorithms. Institute for Drug Resistance: Shifting the Paradigms of Drug Resistance. Shrewsbury, MA, USA.

Frey, K.M., Gray, W.T., Spasov, K.A., Bollini, M., Cisneros, J.A., Gallardo-Masias, R., Jorgensen, W.L., Anderson, K.S. (2013) Structure-based Evaluation of Modified Derivatives in the Catechol Diether Series Targeting HIV-1 Reverse Transcriptase. Cambridge Health Institute: Structure-based Drug Design. Boston, MA, USA.

Frey, K.M. (2014) Computational and Structure-guided Design of Potent Inhibitors of HIV Reverse Transcriptase. Yale Pharmacology Retreat. Orange, CT, USA.

Grants/Contracts

2012-2015 - Structure Activity and Structure Property Relationships of Novel anti-HIV agents, Ruth L. Kirschstein National Research Service Award (NRSA) Postdoctoral Fellowship from the National Institute of Health, Institute of Allergy and Infectious Diseases (Award Number F32 AI104334) 

Honors/Awards

2011 - Boehringer Ingelheim Predoctoral Fellowship Recipient

2011- Doctoral Dissertation Fellowship Recipient, University of Connecticut

2012 & 2013 – Editor Highlighted Publication, Journal of the American Chemical Society

Other Professional Activities

2012-2015 Associate Faculty Member, Biocatalysis Section, Faculty of 1000

2012-2015 Women in Science at Yale, Graduate Student Mentor

2013-2014 Yale Postdoctoral Advisory Committee

 

Research Synopsis

My research focuses on developing computational and experimental approaches to examine drug-target interactions at the molecular level. Specific techniques include computational methods such as molecular modeling, virtual screening, docking, and dynamics, and experimental techniques such as protein x-ray crystallography, assays (cell and enzyme-based), and molecular biology techniques. We are using these methods for drug design, resistance prediction, and polymorphism prediction.

  1. Structure-based Drug Design: Structural information by x-ray crystallography for receptors and enzyme targets facilitates rational drug design. We use 3D structures of both protein-based targets and small molecules to design new compounds with improved affinity, efficacy, selectivity, and physiochemical properties. We are currently using crystal structures of MTA1-HDAC1 to computationally design protein-protein interaction (PPI) inhibitors.
  2. Computational Prediction of Drug Resistance: Drug resistance is a major problem for therapeutics used to treat cancer and infectious diseases. Specific mutations or single amino acid changes in the drug target are often responsible for conferring resistance to several antibiotics, antivirals, and cancer chemotherapies. Using structure-based knowledge and computational techniques, we can retrospectively examine the effects of drug target mutations on the binding of current therapeutics. Our understanding of resistance mutations will guide the design of new resilient drugs and help predict potential cross-resistance to new inhibitors in development.
  3. Approaches to Examine Polymorphisms in Detoxification Enzymes: Polymorphisms that confer amino acid changes in metabolizing enzymes can affect the rates of biotransformation for several drugs. Such metabolizing enzymes include the CYPS in the cytochrome P450 system, cholinesterases/esterases, and detoxification enzyme GST. A computational and experimental approach can be used to assess the effects of such polymorphisms on the metabolism of various drugs and chemicals. We are currently investigating GST polymorphisms and how amino acid changes in the enzyme may affect detoxification rates.