Education

B.Sc. (hons) Chemistry, 1988, University of Canterbury, New Zealand

Ph.D. Chemistry, 1992, University of Canterbury, New Zealand

Research Interests

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. The fundamental understanding of structure and dynamics is critical for successful drug discovery. We co-discovered with Drs. Paula Bates, and Donald Miller, the first anticancer aptamer, AS1411, to reach Phase II clinical trials.

We 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 40 cancer targets that are moving into the laboratories for anticancer activity testing. This has resulted in three collaborative efforts being licensed by a Biotech Company with one going forward to clinical trials.

Lab Personnel

M. Clarke Miller Ph.D., Research Manager, Jon Maguire, Systems Manager.

Huy T Le, MD/PhD student. Indira Chaudhuri PhD, Postdoctoral Fellow.

Selected Publications

Sun, D., Thompson, B., Cathers, B.E., Salazar, M., Kerwin, S.M., Trent, J.O., Jenkins, T.C., Neidle, S., Hurley, L. H.: Inhibition of Human Telomerase by a G-Quadraplex-Interactive Compound. J. Med. Chem. 1997, 40, 2113-2116.

Bates PJ, Kahlon J, Thomas SD, Trent JO & Miller DM: Antiproliferative activity of G-rich oligonucleotides correlates with protein binding. J Biol Chem. 1999 Sep 10;274(37):26369-77

Qu, X, Trent, J.O., Fokt, I., Priebe, W., Chaires, J.B., From the Cover: Allosteric, Chiral-Selective Drug Binding to DNA, PNAS. 97(22):12032-37, 2000.

John O. Trent*, Zi-xuan Wang, James L. Murray, Wenhai Shao, Hirokazu Tamamura, Nobutaka Fujii, Stephen C. Peiper. Lipid Bilayer Simulations of CXCR4 with Inverse Agonists and Weak Partial Agonists. J Biol Chem. Nov 21;278(47):47136-44. Epub 2003 Sep 04.

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. 2005 Aug 16;33(14):4649-59.

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.

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

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

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

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 Jan 9. PMID: 19136469. [Epub ahead of print]

Bates PJ, Laber DA, Miller DM, Thomas SD, Trent JO. Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Exp Mol Pathol. 2009 Jun;86(3):151-64. Epub 2009 Jan 20. PMID: 19454272 [PubMed - indexed for MEDLINE]

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. Epub 2009 Jan 31. PMID: 19454265 [PubMed - indexed for MEDLINE]

Dailey MM, Miller MC, Bates PJ, Lane AN, Trent JO. Resolution and characterization of the structural polymorphism of a single quadruplex-forming sequence. Nucleic Acids Res. 2010 Mar 25. [Epub ahead of print]

Miller MC, Buscaglia R, Chaires JB, Lane AN, Trent JO. Hydration Is a Major Determinant of the G-Quadruplex Stability and Conformation of the Human Telomere 3' Sequence of d(AG(3)(TTAG(3))(3)).J Am Chem Soc. 2010 Nov 18. [Epub ahead of print]PMID:21087016

Clem BF, Clem AL, Yalcin A, Goswami U, Arumugam S, Telang S, Trent JO, Chesney J. A novel small molecule antagonist of choline kinase-α that simultaneously suppresses MAPK and PI3K/AKT signaling. Oncogene. 2011 Jul 28;30(30):3370-80. doi: 10.1038/onc.2011.51. Epub 2011 Mar 21. PMID:21423211

Miller MC, Le HT, Dean WL, Holt PA, Chaires JB, Trent JO. Polymorphism and resolution of oncogene promoter quadruplex-forming sequences.Org Biomol Chem. 2011 Sep 21.PMID:21938285

Holt PA, Buscaglia R, Trent JO, Chaires JB. A Discovery Funnel for Nucleic Acid Binding Drug Candidates. Drug Dev Res. 2011 Mar 1;72(2):178-186.PMID:21566705

Le HT, Miller MC, Buscaglia R, Dean WL, Holt PA, Chaires JB, Trent JO.Not all G-quadruplexes are created equally: an investigation of the structural polymorphism of the c-Myc G-quadruplex-forming sequence and its interaction with the porphyrin TMPyP4. Org Biomol Chem. 2012 Dec 21;10(47):9393-404. doi: 10.1039/c2ob26504d. Epub 2012 Oct 29.PMID:23108607