John O. Trent, Ph.D.
Associate Professor of Medicine and of Biochemistry & Brown Cancer Center
Email John Trent
Phone Number: (502) 852 2194 (Office)
Fax Number: (502) 852 4311
Address: Suite 323, J.G. Brown Cancer Center
527 South Jackson St. Louisville, KY 40202
Ph. D. 1992, University of Canterbury, New Zealand
- Associate Professor, Division of Hematology/Oncology, Dept. of Medicine
- Director, Molecular Modeling Facility, James Graham Brown Cancer Center
- Associate Scientist, James Graham Brown Cancer Center,
- Associate Professor, Division of Internal Medicine, Department of Medicine
- Joint Appointment Associate Professor of Biochemistry and Molecular Biology
- Joint Appointment Associate Professor of Chemistry
- Holt, Andy
- Meier, Jason
- Dailey, Magdalena
- Structure-based drug design, macromolecular molecular dynamics modeling of proteins, DNA and RNA drug discovery.
- My group uses numerous computational techniques to complement experimental approaches aimed at understanding macromolecular interactions. The methods include molecular dynamics, free energy perturbation calculations, and Monte-Carlo methods as applied to real world problems. The combination of modeling techniques with different experimental modalities such as NMR, X-ray diffraction and thermodynamic methods is synergistic, and is the key to understanding structure and function. We have successfully modeled the structure of the nucleolin binding quadruplex, as verified by biophysical studies such as CD (with P. Bates), analytical ultracentrifugation and NMR (with A. Lane). We also have produced detailed rhodopsin-based homology models of the CCR5 and CXCR4 chemokine receptors, embedded in a complete, solvated lipid bilayer, that successfully account for the saturation mutation data obtained by Dr. S. C. Peiper at the Brown Cancer Center (now at Georgia Medical College, Augusta). We have a strong interest in quadruplex structure and as a drug target and collaborate with Dr. J. B. Chaires on the biophysical aspect of this work.
- We also have enhanced our drug discovery program by establishing a distributing computing Grid for virtual screening. The Grid development is in collaboration with Dataseam and uses thousands of computer processors in schools across the Commonwealth of Kentucky. It is now routine in my laboratory to screen millions of potential compounds against a cancer target in days. We have successfully screened over 60 cancer targets that are moving into the laboratories for anticancer activity testing.
- Dailey MM, Hait C, Holt PA, Maguire JM, Meier JB, Miller MC, Petraccone L, Trent JO. Structure-based drug design: from nucleic acid to membrane protein targets. Exp Mol Pathol. 2009 Jun;86(3):141-50
- Holt PA, Ragazzon P, Strekowski L, Chaires JB, Trent JO. Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform. Nucleic Acids Res. 2009 Mar;37(4):1280-1287.
- Duan X, Trent JO, Ye H. Targeting the SUMO E2 conjugating enzyme Ubc9 interaction for anti-cancer drug design. Anticancer Agents Med Chem. 2009 Jan;9(1):51-4. PMID: 19149481
- Petraccone L, Trent JO, Chaires JB. The tail of the telomere. J Am Chem Soc. 2008 Dec 10;130(49):16530-2. PMID: 19049455
- Winner M, Meier J, Zierow S, Rendon BE, Crichlow GV, Riggs R, Bucala R, Leng L, Smith N, Lolis E, Trent JO, Mitchell RA. A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells. Cancer Res. 2008 Sep 15;68(18):7253-7. PMID: 18794110
- Walraven JM, Trent JO, Hein DW. Structure-function analyses of single nucleotide polymorphisms in human N-acetyltransferase 1. Drug Metab Rev. 2008;40(1):169-84. Review. PMID: 18259988
- Holt PA, Chaires JB, Trent JO. Molecular docking of intercalators and groove-binders to nucleic acids using Autodock and Surflex. J Chem Inf Model. 2008 Aug;48(8):1602-15. Epub 2008 Jul 22. PMID: 18642866
- Lane AN, Chaires JB, Gray RD, Trent JO. Stability and kinetics of G-quadruplex structures. Nucleic Acids Res. 2008 Oct;36(17):5482-515. PMID: 18718931
- Mekmaysy CS, Petraccone L, Garbett NC, Ragazzon PA, Gray R, Trent JO, Chaires JB. Effect of O6-methylguanine on the stability of G-quadruplex DNA. J Am Chem Soc. 2008 May 28;130(21):6710-1. Epub 2008 May 1. PMID: 18447358
- Zarebski A, Velu CS, Baktula AM, Bourdeau T, Horman SR, Basu S, Bertolone SJ, Horwitz M, Hildeman DA, Trent JO, Grimes HL. Mutations in growth factor independent-1 associated with human neutropenia block murine granulopoiesis through colony stimulating factor-1. Immunity. 2008 Mar;28(3):370-80. Epub 2008 Mar 6.
- Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, Rasku MA, Arumugam S, Dean WL, Eaton J, Lane A, Trent JO, Chesney J. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther. 2008 Jan;7(1):110-20.
- Basu S, Jala VR, Mathis S, Rajagopal ST, Del Prete A, Maturu P, Trent JO, Haribabu B. Critical role for polar residues in coupling leukotriene B4 binding to signal transduction in BLT1. J Biol Chem. 2007 Mar 30;282(13):10005-17. Epub 2007 Jan 21.
- Napier KB, Wang ZX, Peiper SC, Trent JO. CCR5 interactions with the variable 3 loop of gp120. J Mol Model 13(1):29-41, 2006.
- Galande AK, Bramlett KS, Trent JO, Burris TP, Wittliff JL, Spatola AF. Potent inhibitors of LXXLL-based protein-protein interactions. Chembiochem 6(11):1991-8, 2005
- Li J, Correia JJ, Wang L, Trent JO, Chaires JB. Not so crystal clear: the structure of the human telomere G-quadruplex in solution differs from that present in a crystal. Nucleic Acids Res 33(14):4649-59, 2005
Patents & Licenses:
- “Antiproliferative Activity of G-Rich Oligonucleotides and Method of Using Same to Bind to Nucleolin” Donald M. Miller, Paula J. Bates, John O. Trent. Filed August 1999
- "Novel Cancer Marker". Inventors: P.Bates, D. Miller, J. Trent, X. Xu. Filed January 2002
- ULRF ref. #05037: Trent, Mitchell, and Meier. Patent Cooperation Treaty (PCT) application, # PCT/US07/69672; MACROPHAGE MIGRATION INHIBITORY FACTOR ANTAGONISTS AND METHODS OF USING SAME; filed May 24, 2007; Status: Pending, but National Stage filing decision coming soon--November 26, 2008
- ULRF ref. # 08065: Trent, Mitchell, and Chand (Note: Joint technologies--ULRF and ACT).U.S. Provisional patent application # 61/042,358; NOVEL 4-IODO-6-ARYL- AND SUBSTITUTED-ARYL-PYRIMIDINES USEFUL FOR THE TREATMENT OF MACROPHAGE INHIBITION; filed April 4, 2008; Status: PENDING.
- U.S. Provisional patent application # 61/088,763; NOVEL 4-IODO-6-ARYL- AND SUBSTITUTED-ARYL-PYRIMIDINES USEFUL FOR THE TREATMENT OF MACROPHAGE INHIBITORY FACTOR (MIF)-IMPLICATED INFLAMMATORY DISEASES AND CANCERS; filed August 14, 2008; Status: PENDING
- LICENSE FOR THE ABOVE MIF TECHNOLOGIES: With LICENSEE = Advanced Cancer Therapeutics (ACT); execution date - 3/26/2008; Effective date: January 17, 2008.
- ULRF ref. #07010: Trent, Chesney, Meier, Telang, and Clem. U.S. Non-Provisional patent application # 12/141,751; FAMILY OF PFKFB3 INHIBITORS WITH ANTI-NEOPLASTIC ACTIVITIES; filed June 18, 2008; and PCT application # PCT/US08/007594; FAMILY OF PFKFB3 INHIBITORS WITH ANTI-NEOPLASTIC ACTIVITIES; filed June 18, 2008. Status of U.S. nonprov and PCT applications: Both PENDING.
- LICENSE: With LICENSEE = Advanced Cancer Therapeutics (ACT); execution date - 3/26/2008; Effective date: January 17, 2008.