In collaboration with a variety of synthetic organic and medicinal chemistry groups, we are applying several computational methods to facilitate the design of enzyme inhibitors and other potential drug compounds.
One technique we employ is automated docking of potential inhibitor structures into enzyme active sites. We are experimenting with different docking algorithms as well as different approaches for applying these methods to high-throughput screening of libraries of potential inhibitors.
We are also using "principal moment of inertia" analyses to characterize and quantify the diversity of compound libraries.
In addition, we are using quantum chemical methods to rationalize and predict stereoselectivities for reactions used to synthesize potentially active compounds, as well as conformational preferences of potential drugs.
Yoo, C. L.; Olmstead, M. M.; Tantillo, D. J.; Kurth, M. J. Tetrahedron Lett. 2006, 47, 477-481: "Synthesis of 2H-Pyrroles via the 1,3-Dipolar Cycloaddition of Nitrile Ylides with Acrylamides"
Meadows, D. C.; Tantillo, D. J.; Gervay-Hague, J. ChemMedChem 2006, 1, 959-964: "Correlation of Biological Activity with Active Site Binding Modes of Geminal Disulfone HIV-1 Integrase Inhibitors"
Carpenter, R. D.; DeBerdt, P. B.; Holden, J. B.; Milinkevich, K. A.; Min, T.; Willenbring, D.; Fettinger, J. C.; Tantillo, D. J.; Kurth, M. J. J. Comb. Chem. 2008, 10, 225-229: "Design and Synthesis of Propeller-shaped Dispiroisoxazolopiperidinochromanones"
Yu, G. J.; Yoo, C. L.; Yang, B.; Lodewyk, M. W.; Meng, L.; El-Idreesy, T. T.; Fettinger, J. C.; Tantillo, D. J.; Verkman, A. S.; Kurth, M. J. J. Med. Chem. 2008, 51, 6044-6054: "Potent s-cis-Locked Bithiazole Correctors of (delta)F508-Cystic Fibrosis Transmembrane Conductance Regulator Cellular Processing for Cystic Fibrosis Therapy"
Meng, L.; Wang, S. C.; Fettinger, J. C.; Kurth, M. J.; Tantillo, D. J. Eur. J. Org. Chem. 2009, 1578-1584: "Controlling Selectivity for Cycloadditions of Nitrones and Alkenes Tethered by Benzimidazoles: Combining Experiment and Theory"
Lodewyk, M. W.; Kurth, M. J.; Tantillo, D. J. J. Org. Chem. 2009, 74, 4804-4811: "Mechanisms for Formation of Diazocinones, Pyridazines, and Pyrazolines from Tetrazines - Oxyanion-Accelerated Pericyclic Cascades?"
Ye, L.; Haddadin, M. J.; Lodewyk, M. W.; Ferreira, A.; Fettinger, J. C.; Tantillo, D. J.; Kurth, M. J. Org. Lett. 2010, 12, 164-167: "Cyclopenta[b]pyrroles from Triazines - Synthetic and Mechanistic Studies"
Butler, J. D.; Conrad, W. E.; Lodewyk, M. W.; Fettinger, J. C.; Tantillo, D. J.; Kurth, M. J. Org. Lett. 2010, 12, 3410-3413: "Synthesis of Substituted Chromanones: An Organocatalytic Aldol/oxa-Michael Reaction"
Guggenheim, K. G.; Butler, J. D.; Painter, P. P.; Lorsbach, B. A.; Tantillo, D. J.; Kurth, M. J. J. Org. Chem. 2011, 76, 5803-5812: "Synthesis of Spiro-fused Pyrazolidoisoxazolines"
Biggs-Houck, J. E.; Davis, R. L.; Wei, J.; Mercado, B. Q.; Olmstead, M. M.; Tantillo, D. J.; Shaw, J. T. J. Org. Chem. 2012, 77, 160-172: "Carbon-Carbon Bond-Forming Reactions of alpha-Thioaryl Carbonyl Compounds for the Synthesis of Complex Heterocyclic Molecules"
Knapp, J. M.; Wood, A. B.; Phuan, P.-W.; Lodewyk, M. W.; Tantillo, D. J.; Verkman, A. S.; Kurth, M. J. J. Med. Chem. 2012, 55, 1242-1251: "Structure-Activity Relationships of Cyanoquinolines with Corrector-Potentiator Activity in (delta)F508-Cystic Fibrosis Transmembrane Conductance Regulator Protein"
Avila, B.; El-Dakdouki, M. H.; Nazer, M. Z.; Harrison, J. G.; Tantillo, D. J.; Haddadin, M. J.; Kurth, M. J. Tetrahedron Lett. 2012, 53, 6475–6478: "Acid and Base Catalyzed Davis-Beirut Reaction: Experimental and Theoretical Mechanistic Studies and Synthesis of Novel 3-Amino-2H-indazoles"
Sorto, N. A.; Painter, P. P.; Fettinger, J. C.; Tantillo, D. J.; Shaw, J. T. Org. Lett. 2013, 15, 2700-2703: "Design and Synthesis of Mimics of the T7-loop of FtsZ"
Harrison, J. G..; Zheng, Y. B.; Beal, P. A.; Tantillo, D. J. ACS Chem. Biol. 2013, 8, 2354-2359: "Computational Approaches to Predicting the Impact of Novel Bases on RNA Structure and Stability"
Onizuka, K.; Harrison, J. G.; Ball-Jones, A. A.; Ibarra-Soza, J. M.; Zheng, X.; Ly, D.; Lam, W.; Mac, S.; Tantillo, D. J.; Beal, P. A. J. Am. Chem. Soc. 2013, 135, 17069-17077: "Short Interfering RNA Guide Strand Modifiers from Computational Screening"
Williams, D. T.; Atwater, B. A.; Bawel, S. A.; Ke, P.; Gutierrez, O.; Tantillo, D. J. Org. Lett. 2014, 16, 468-471: "Stereocontrol in Asymmetric SE' Reactions of gamma-Substituted-alpha,beta-Unsaturated Aldehydes"
Patra, D.; Palazzo, T. A.; Malaeb, N. N..; Haddadin, M. J.; Tantillo, D. J.; Kurth, M. J. J. Fluorescence 2014, 24, 1285-1296: "Cyclic Azacyanines: Experimental and Computational Studies on Spectroscopic Properties and Unique Reactivity"
Roth, A.; Ott, S.; Farber, K. M.; Palazzo, T. A.; Conrad, W. E.; Haddadin, M. J.; Tantillo, D. J.; Cross, C. E.; Eiserich, J. P.; Kurth, M. J. Bioorg. Med. Chem. 2014, 22, 6422-6429: "Inhibition of Myeloperoxidase: Evaluation of 2H-Indazoles and 1H-Indazolones"
Ye, L.; Hu, B.; El-Badri, F.; Hudson, B.M.; Phuan, P.-W.; Verkman, A. S.; Tantillo, D. J.; Kurth, M. J. Bioorg. Med. Chem. Lett. 2014, 24, 5840-5844: "(delta)F508-CFTR Correctors: Synthesis and Evaluation of Thiazole-Tethered Oxazoles, Oxadiazoles, and Thiadiazoles"
Palazzo, T. A.; Patra, D.; Yang, J. S.; El Khoury, E.; Appleton, M. G.; Haddadin, M. J.; Tantillo, D. J.; Kurth, M. J. Org. Lett. 2015, 17, 5732-5735: "Dibenzonaphthyridinones: Heterocycle-to-Heterocycle Synthetic Strategies and Photophysical Studies"
Wilkerson-Hill, S. M.; Fisher, E. L.; Yu, D.; Painter, P. P.; Tantillo, D. J.; Sarpong, R.; Hein, J. E. J. Am. Chem. Soc. 2017, 139, 10569-10577: "On the Mechanism of No-metal-added Heterocycloisomerization of Alkynylcyclopropylhydrazones: A Synthesis of Cycloheptane-fused Aminopyrroles Facilitated by Copper salts at Trace Loadings"
Lim, N.-K.; Weiss, P.; Li, B. X.; McCulley, C. H.; Hare, S. R.; Bensema, B. L.; Palazzo, T. A.; Tantillo, D. J.; Zhang, H.; Gosselin, F. Org. Lett. 2017, 19, 6212-6215: "Synthesis of Highly Stereodefined Tetrasubstituted Acyclic All-Carbon Olefins via a syn-Elimination Approach"
Zhu, J. S.; Kraemer, N.; Shatskikh, M. E.; Li, C. J.; Son, J.-H.; Haddadin, M. J.; Tantillo, D. J.; Kurth, M. J. Org. Lett. 2018, 20, 4736-4739: "N-N Bond Formation between 1°-Amines and Nitrosos: Direct Synthesis of 2-Substitiuted Indazolones with Mechanistic Insights"
Kraemer, N.; Li, C. J.; Zhu, J. S.; Larach, J. M.; Tsui, K. Y.; Tantillo, D. J.; Haddadin, M. J.; Kurth, M. J. Org. Lett. 2019, 21, 6058-6062: "Davis–Beirut Reaction: A Photochemical Brønsted Acid Catalyzed Route to N-Aryl 2H-Indazoles"
Barnych, B.; Singh, N.; Negrel, S.; Zhang, Y.; Magis, D.; Roux, C.; Hua, X.; Ding, Z.; Morisseau, C.; Tantillo, D. J.; Siegel, J. B.; Hammock, B. D. Eur. J. Med. Chem. 2020, 193, 112206: "Development of Potent Inhibitors of the Human Microsomal Epoxide Hydrolase"
Son, J.-H.; Phuan, P.-W.; Zhu, J. S.; Lipman, E.; Cheung, A.; Tsui, K. Y.; Tantillo, D. J.; Verkman, A. S.; Haggie, P. M.; Kurth, M. J. Eur. J. Med. Chem. 2021, 209, 112888: "1-Benzylspiro[piperidine-4,1'-pyrido[3,4-b]indole] 'Co-potentiators' for Minimal Function CFTR Mutants," invited contribution to special issue on "Pharmacological Approaches to Cystic Fibrosis"
Soor, H. S.; Diaz, D. B.; Tsui, K. Y.; Calvopiña, K..; Bielinski, M.; Tantillo, D. J.; Schofield, C. J.; Yudin, A. K. J. Org. Chem. 2022, 87, 94-102: "Synthesis and Application of Constrained Amidoboronic Acids Using Amphoteric Boron-containing Building Blocks"
Jacquelyn Gervay-Hague, Dean J. Tantillo and D. Christopher Meadows: "Computational Studies and Biological Evaluation of Geminal Disulfones as HIV-1 Integrase Inhibitors." Lecture presented by Jacquelyn Gervay-Hague at the 230th ACS National Meeting, Washington, DC, August 28-September 1, 2005.
Liping Meng, Selina C. Wang, James C. Fettinger, Mark J. Kurth, and Dean J. Tantillo: "Experiment and Theory Study on the Cycloadditions of Nitrones and Alkenes Tethered by Benzimidazoles." Poster presented by Liping Meng at the 237th ACS National Meeting, Salt Lake City, UT, March 22-26, 2009; paper ORGN 150.
Philip P. Painter and Dean J. Tantillo: "Eclipsing Transition States and Their Role in Chiral Imidazoline Racemization." Poster presented by Phil Painter at the SYLICCO.09 Symposium, Davis, CA, July 23, 2009.
Henry B. Wedler, Christian S. Hamann, and Dean J. Tantillo: "TheTheoretical Hydration Energues of Biologically Relevant alpha-Ketoamides." Poster presented by Hoby Wedler at the SYLICCO.09 Symposium, Davis, CA, July 23, 2009.
Handeep Kaur and Dean J. Tantillo: "The Bacteria's Gift: A Mechanistic Study of the Synthesis of Pseudomonine." Poster presented by Handeep Kaur at the SYLICCO.09 Symposium, Davis, CA, July 23, 2009.
Christian S. Hamann, Nichole A. Reed, and Dean J. Tantillo: "Modeling the Conformational Isomerization of an Atropisomeric Farnesyl Transferase Inhibitor." Poster presented by Chris Hamann at the SYLICCO.09 Symposium, Davis, CA, July 23, 2009.
Nicole A. Reed, Dean J. Tantillo and Christian S. Hamann: "Modeling the Conformational Isomerization of an Atropisomeric Farnesyl Transferase Inhibitor." Lecture presented by Chris Hamann at the 239th ACS National Meeting, San Francisco, CA, March 21-25, 2010; paper ORGN 359.
Nohemy A. Sorto, Philip Painter, Dean J. Tantillo and Jared T. Shaw: "Synthesis of Potential Bacterial Cell Division Modulators." Poster presented by Nohemy Sorto and Phil Painter at the Bradford Borge Weekend, University of California, Davis, CA, February 18-19, 2011.
Nohemy A. Sorto, Philip Painter, Dean J. Tantillo and Jared T. Shaw: "Synthesis of Potential Bacterial Cell Division Modulators." Poster presented by Nohemy Sorto and Phil Painter at the R. Bryan Miller Symposium, UC Davis, Davis, CA, March 3-4, 2011.
