Professor, Organic/Medicinal and Combinatorial Chemistry
Professor of Chemistry, and Associate Director of Medicinal Chemistry, UAB Center for Biophysical Sciences and Engineering; (b. 1950), obtained a B.S. degree in chemistry at the University of West Florida (1972). He then pursued graduate studies under Professor Edward E. Smissman in the Department of Medicinal Chemistry at the University of Kansas (Ph.D., 1977). His work at Kansas involved the design and synthesis of anticonvulsant agents, and he remained there for a postdoctoral appointment with Dr. Gary L. Grunewald. He joined the Department of Chemistry at UAB in 1979. Outside interests include coastal sailing and hiking.
The research theme of this laboratory is the design and synthesis of potential new drugs using protein structure and molecular modeling/computational tools. Students working on these problems are engaged in organic synthesis, molecular modeling, and/or in vitro biological evaluations.
Ongoing projects include:
- Antibacterial Drugs and Biodefense. A tremendous need exists to develop new antibacterial drugs, because of alarming rates of bacterial antibiotic resistance and the potential use of bacteria such as anthrax in bioterrorism or biowarfare. We have targeted the enzyme NAD synthetase for this purpose and have used the crystal structure along with in silico screening and compound library synthesis for identifying new structural classes of compounds with potent antibacterial activity. (funded by NIH).
- Voltage-Gated Sodium Channel (VGSC) Ligands for Cancer Therapy. We utilized 3D QSAR (CoMFA) to develop a highly predictive model for the drug binding site on this protein, which successfully correlates the binding activities for a large number of compounds. This model allowed us to design new structures that are among the most potent known small organic molecule ligands for this protein. We are now exploring the activities of these compounds in prostate, breast, and other highly metastatic cancers of epithelial origin.
- Drugs for treating or preventing cancer. The identification of nuclear retinoic acid receptors (RARs & RXRs) as ligand-modulated transcriptional factors led us to study chemopreventive effects of retinoic acid (vitamin A) analogs. In these studies we have designed vitamin A analogs that are selective for individual nuclear receptors and are less toxic than the natural vitamin. In particular, our new rexinoids (RXR-selective retinoids) show exciting activity in preventing breast cancer in a rat model, and our lead compound UAB-30 is being sponsored by the National Cancer Institute for a phase I human clinical trial. (funded by NIH)
Drugs for avian influenza. Neuraminidase is a surface enzyme on influenza virus that is essential for its infectivity cycle. We have utilized the iterative process of structure-based drug design to produce simple benzoic acid derivatives that are potent inhibitors of the viral protein and inhibit viral reproduction in cell culture. (funded by NIH)
Desphande, A., Xia, G., Boerma, L. J., Vines, K. K., Atigadda, V. R., Lobo-Ruppert, S., Grubbs,. C. J., Moeinpour, F. L., Smith, C. D., Christov, K., Brouillette, W. J., Muccio, D. D., Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention., Bioorg Med Chem., 2014, 22(1):178-85., PMID: 24359708.
Atigadda, V. R., Xia, G., Deshpande, A., Boerma, L. J., Lobo-Ruppert, S. M., Grubbs, C. J., Smith, C. D., Brouillette, W. J., Muccio, D. D., Methyl-Substitution of a Rexinoid Agonist Improves Potency and Reveals Site of Lipid Toxicity., J Med Chem., 2014, May 6. [Epub ahead of print], PMID: 24801499
Zha, C., G.B. Brown, and W.J. Brouillette, A highly predictive 3D-QSAR model for binding to the voltage-gated sodium channel: design of potent new ligands. Bioorg Med Chem, 2014. 22(1): p. 95-104. Epub 2013 Dec 6. PMID: 24359708.
Venkatramani, L., Johnson, E.S., Kolavi, G., Air, G.M. Brouillette, W.J. and Mooers, B.H.M. (2012) Crystal Structure of a New Benzoic Acid Inhibitor of influenza Neuraminidase Bound with a New Tilt Induced by Overpacking Subsite C6”. BMC Structural Biology 12(1), 7-17.
Li, Y., Silamkoti, A., Kolavi, G., Mou, L., Gulati, S., Air, G.M., and Brouillette, W.J. (2012) “Pyrrolidinobenzoic Acid Inhibitors of Influenza Virus Neeuraminidase: The Hydrophobic Side Chain Influences Type A Subtype Selectivity” Bioorgnaic & Medicinal Chemistry 20(14) 4582-4589.
Kang S, Mou L, Lanman J, Velu S, Brouillette WJ, Prevelige PE Jr. "Synthesis of biotin-tagged chemical cross-linkers and their applications for mass spectrometry," Rapid Commun Mass Spectrom. 2009, 23(11), pp 1719-26.
Moro WB, Yang Z, Kane TA, Zhou Q, Harville S, Brouillette CG, Brouillette WJ. "SAR Studies for a New Class of Antibacterial NAD Biosynthesis Inhibitors," J Comb Chem. 2009, 11 (4), pp 617-625.
Moro WB, Yang Z, Kane TA, Brouillette CG, Brouillette WJ. "Virtual screening to identify lead inhibitors for bacterial NAD synthetase (NADs)." Bioorg Med Chem Lett. 2009, 19(7), pp 2001-5.
Jiang W, Deng W, Bailey SK, Nail CD, Frost AR, Brouillette WJ, Muccio DD,Grubbs CJ, Ruppert JM, Lobo-Ruppert SM, "Prevention of KLF4-mediated tumor initiation and malignant transformation by UAB30 rexinoid," Cancer Biol Ther. 2009, 8(3), pp 289-98.
Lu S, Smith CD, Yang Z, Pruett PS, Nagy L, McCombs D, Delucas LJ, Brouillette WJ, Brouillette CG. "Structure of nicotinic acid mononucleotide adenylyltransferase from Bacillus anthracis." Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008, 64(Pt 10), pp 893-8.
Love WK, Deangelis JT, Berletch JB, Phipps SM, Andrews LG, Brouillette WJ, Muccio DD, Tollefsbol TO, "The Novel Retinoid, 9cUAB30, Inhibits Telomerase and Induces Apoptosis in HL60 Cells," Transl Oncol. 2008, 1(3),l pp 148-52.