Dr. Marnett has research interests in the areas of protein structure and function, nucleic acid chemistry, drug design and synthesis, and chemical genomics. Much of his work focuses on the biochemistry and molecular biology of oxidation of natural and synthetic chemicals. Areas of interest include: mechanisms of oxidation of arachidonic acid and endocannabinoids by cyclooxygenase and lipoxygenase enzymes, design, synthesis, and biochemical evaluation of lipoxygenase and selective cyclooxygenase-2 (COX-2) inhibitors; chemistry and biology of DNA damage by lipid oxidation products; and endogenous pathways of DNA damage in the genesis of human cancer.

Cyclooxygenase-2 (COX-2) is the molecular target of non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors. Dr. Marnett's laboratory has combined structural analysis with functional studies to define the molecular determinants of the interaction of ligands (substrates and inhibitors) with COX-2. For example, the lab recently reported the identification of a critical H-bonding interaction that leads to the selectivity of aspirin for acetylation of Ser-530 in COX-2. Many NSAIDs are aralkyl carboxylic acids. Comparative analysis of the effect of site-directed mutation of active site residues on the binding of substrates and inhibitors to COX-1 and COX-2 led us to hypothesize that neutral derivatives of esters and amides would bind selectively to COX-2. They tested this hypothesis by synthesizing a series of neutral derivatives of NSAIDs and demonstrating increases in selectivity for COX-2 of several orders of magnitude. Dr. Marnett is exploiting this discovery to prepare novel COX-2 inhibitors as anti-inflammatory drugs and cancer preventive agents.

Recent publications include:

• Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.
  Windsor MA, Valk PL, Xu S, Banerjee S, Marnett LJ.
  Bioorg Med Chem Lett. 2013 Nov 1;23(21):5860-4. doi: 10.1016/j.bmcl.2013.08.097. Epub 2013 Sep 6.

• Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation.
  Hermanson DJ, Hartley ND, Gamble-George J, Brown N, Shonesy BC, Kingsley PJ, Colbran RJ, Reese J, Marnett LJ, Patel S.
  Nat Neurosci. 2013 Sep;16(9):1291-8. doi: 10.1038/nn.3480. Epub 2013 Aug 4.

• Substrate-Selective Inhibition of Cyclooxygenase-2: Development and Evaluation of Achiral Profen Probes.
  Windsor MA, Hermanson DJ, Kingsley PJ, Xu S, Crews BC, Ho W, Keenan CM, Banerjee S, Sharkey KA, Marnett LJ.
  ACS Med Chem Lett. 2012 Sep 13;3(9):759-763. Epub 2012 Aug 15.

Our May 2014 meeting is generously sponsored by:

Silver Sponsors

BioreclamationIVT

Optivia Bio

Bronze Sponsors

Waters

For more information on sponsoring SCDMDG, please refer to our sponsorship guidelines.

Prior presentations:

Note: slides are displayed in a new window, left-click to advance, right-click to go back.

Speaker	PDF	Topic	Date
Lawrence J. Lesko, Ph.D., F.C.P.		Drug Interaction Studies: Differences and Similarities in How to Meet the Regulatory Expectations in FDA Guidance and EMA Guidelines	May 14, 2013
Thomas Tozer, Ph.D.		Pharmacokinetics of Protein Drugs	October 23, 2012
Shujuan Chen		Application of Animal Models for Human Glucuronidation	October 23, 2012
Caroline Decker		The Use of Modified Bacterial CYPs for Metabolite Generation	October 23, 2012
Mary Dwyer, Ph.D.		Cancer Therapeutics: A Novel Approach	October 23, 2012
Justin Hoffman PharmD MS		Population Pharmacokinetics (PK) of LopinavirDuring Pregnancy and Postpartum	October 23, 2012
David A. Yee		Observations on the Urine Metabolic Ratio of Oxymorphone to Oxycodone in Pain Patients	October 23, 2012
Nabil Hanna, Ph.D.		The Discovery and Development of Rituxan	April 10, 2012
Dr. Richard Kim		Drug Transporters: In Vitro and Knockout Model Systems, Pharmacogenomics, and Clinical Relevance	April 19, 2011
Dr. Jerry Galluppi		Biotherapeutic Drug Research and Development: A Growing Role for the DMPK Scientist	October 5, 2010
Dr. Dennis Smith		Does drug metabolism hold its future in its own hands?	April 27, 2010
Dr. Paul F. Hollenberg		Mechanism-Based Inactivation of Human Cytochromes P450	October 6, 2009
Dr. Jack H. Dean Dr. Thomas Baillie		Challenges & Opportunities in Drug Development from a Drug Safety and Metabolism Perspective	May 19, 2009
Eric Johnson, Ph.D.		Characterization of Substrate/Inhibitor Binding to Drug-Metabolizing Cytochrome P450 Monooxygenases using X-ray Crystallography	September 30, 2008
Dr. Kenneth E. Thummel, Ph.D.		Regulation Of Intestinal CYP3A By VDR: Implications And Safety Of Oral Therapeutics	May 7, 2008
Dr. Anthony Lu, Ph.D.		Why Is The Liver Microsomal Cytochrome P450 Such A Versatile And Unique Enzyme?	September 12, 2007
Dr. Scott Obach, Ph.D.		Leveraging ADME Data In Metabolites In Safety Testing (MIST)	April 18, 2007
Dr. Sidney Nelson, Ph.D.		Drug Metabolism and Chemical Structural Alerts	September 27, 2006
Richard B. Kim, MD		Relevance and Utility of Transporters to Drug Discovery and Development	September 21, 2005
Dr. Frederick P. Guengerich, Ph.D.		Human Cytochrome P450 2A6 as a Case History:  Flavors, Smoke, Blue Roses, New Drugs & Basics of a P450	April 27, 2005
Dr. Leslie Benet, Ph.D.		Predicting Drug Disposition via Application of BCS: Transport/Absorption/Elimination Interplay and BDDCS	September 29, 2004
Dr. Christopher A. Lipinski, Ph.D.		ADME/Tox: How Low Can You Go And How Do You Recover?	April 21, 2004