INFORMATION
| Keynote Speaker – Prof Richmond Sarpong (UC Berkeley)
Prof. Sarpong’s laboratory focuses on the synthesis of bioactive complex organic molecules, with a particular focus on secondary metabolites that come from marine or terrestrial flora and fauna. These natural products continue to serve as the inspiration for new medicines Industrial Speakers – Mark Mantell: Scientist at GSK- DNA Encoded Technology and Philip Clayman: Investigator at GSK – Enzyme Engineering and Biocatalysis Student/Postdoc Flash Presentations. Sign up here for the Career Panel, Networking Lunch, and Poster Sessions. =========================================================== SCHEDULE 9 – 10 a.m. Career Panel with GSK Scientists RM 2401 (Coffee and Greenbush donuts provided) 10 – 10:30 a.m. Coffee & donuts Outside Seminar Hall 10:30 a.m. Symposium Introduction Seminar Hall 10:45 a.m. – 12:30 p.m. UW Flash Talks (details below) Katie Weber (Yoon Group) Y Dang (Wickens Group) Dr. Xianyuan Zhao (Yang Group) Irene Stoutland (Blackwell Group) Christopher Hanneman (Stahl Group) Lauren Ehehalt (Weix Group) 12:30 – 2 p.m. Networking Lunch (food provided) Learning Studio (1435 North Tower) 2 – 3:20 p.m. GSK Presentations (details below) Dr. Mark Mantell (DNA Encoded Technology) Dr. Philip Clayman (Enzyme Engineering & Biocatalysis) 3:30 – 5 p.m. Keynote Speaker (details below) Prof. Richmond Sarpong 5 – 6:30 p.m. Poster Session – Drinks and light snacks provided North Tower Atrium =========================================================== DETAILS Flash Presentations Name: Katie Weber Title: Visible Light-Promoted Direct Lactonization Enabled By 1,5–Hydrogen Atom Transfer
—————————————————————————————- Name: Y Dang Title: Formate-enabled Alkene Carboxylation-Alkylation via Radical Polar Crossover
—————————————————————————————- Name: Dr. Xianyuan Zhao Title: Investigating proton transfer wire in human transketolase for an explanation of its cooperativity
Abstract: The hybrid quantum mechanics/molecular mechanics (QM/MM) approach, which combines the accuracy of quantum mechanical (QM) methods with the efficiency of molecular mechanics (MM) methods, is widely used in the study of complex systems. However, past QM/MM implementations often neglect or face challenges in addressing nuclear quantum effects, despite their crucial role in many key chemical and biological processes. Recently, our group developed the constrained nuclear-electronic orbital (CNEO) theory, a cost-efficient approach that accurately addresses nuclear quantum effects, especially quantum nuclear delocalization effects. In this work, we integrate CNEO with the QM/MM approach through the electrostatic embedding scheme and apply the resulting CNEO QM/MM to two hydrogen-bonded complexes in both gas and aqueous phases. We find that both solvation effects and nuclear quantum effects significantly impact hydrogen bond structures and dynamics. Notably, in the glutamic acid – glutamate complex, which mimics a low barrier hydrogen bond in human transketolase, CNEO QM/MM accurately predicts nearly equal proton sharing between the two residues. With an accurate description of both quantum nuclear delocalization effects and environmental effects, CNEO QM/MM is a promising new approach for simulating complex chemical and biological systems. —————————————————————————————- Name: Irene Stoutland Title: Investigations into the structural determinants of associative and dissociative mechanisms in LuxR-type quorum sensing receptors
Abstract: LuxR/I-type quorum sensing (QS) regulates a variety of cell density-dependent phenotypes, including biofilm formation, virulence, and symbiosis, in many common species of Gram-negative bacteria. Small molecules that target QS are of interest as chemical probes to better understand QS systems and for potential applications in antivirulence, antibiofouling, and synthetic biology. To this end, the Blackwell research lab has developed a variety of small molecule agonists and antagonists targeting LuxR-type QS receptors. These intracellular receptors are transcription factors that are activated by binding to small molecule autoinducer ligands. The general lack of information about LuxR receptor structure and the precise mechanisms of action of small molecule LuxR modulators, antagonists in particular, is a significant barrier to the design of more potent, specific, and stable probes. The current study aims to determine the structural features that differentiate LuxR receptors that are most active in the presence of ligand (associative) and those that are most active in the absence of ligand (dissociative). Through the design and generation of “chimeric” LuxRs combining domains from the associative LasR receptor of Pseudomonas aeruginosa, the dissociative EsaR receptor of Pantoea stewartii, and/or the dissociative ExpR2 receptor of Pectobacterium versatile, we have found that the ligand-binding domain, rather than the DNA-binding domain, determines whether a LuxR-type receptor is more active in the presence of ligand or in its absence. Select synthetic LasR antagonists were found to maintain their activity in chimeras with interchanged, dissociative-type DNA-binding domains. In addition, a complementary mutagenesis approach revealed that LasR, EsaR, and ExpR2 have divergent responses to changes in the length of the linker region between the ligand-binding and DNA-binding domains, which has broader implications for our understanding of signal transduction in general in this class of receptors. Collectively, these results provide a deeper understanding of the modes by which small molecules control the activity of mechanistically distinct LuxR-type receptors and suggests new routes for the manipulation of LuxR/I-type QS network. —————————————————————————————- Name: Christopher M. Hanneman Title: Copper-Nitroxyl Catalyzed α-Oxygenation of Cyclic Secondary Amines
—————————————————————————————- Name: Lauren Ehehalt Title: Using Metal-Organic Frameworks as Efficient Carbon Monoxide Removal Reagents in Decarbonylative Cross-Electrophile Coupling
Abstract: Current methods of decarbonylative cross-couplings rely on elevated temperatures or near-stoichiometric equivalences of precious metal salt additives to promote decarbonylation. However, these methods pose problems in scale-up, both from a cost and safety perspective. There exists, then, a need for a safe, recyclable reagent to promote decarbonylation at more mild temperatures. We report the use of a nickel-based Metal Organic Framework (MOF) as an efficient CO removal reagent and highlight its utility in decarbonylative cross-electrophile couplings. By using an In-Ex Tube and Phosphonium Ionic Liquid, the MOF remains separated from the reaction mixture, allowing for immediate transfer and reuse in subsequent reactions. Through experimental data and DFT calculations, the high binding affinity of CO(g) to the MOF is notable, providing further insights into its utility. =========================================================== GSK Presentations Speaker: Dr. Mark Mantell, Scientist at GSK- DNA Encoded Technology Title: DNA-compatible Ugi 4C-3C Reactions
Abstract: Developing new on-DNA reactions is paramount to the development of new encoded libraries in the pursuit of novel pharmaceutical lead compounds. Lactam-containing molecules have been shown to be effective in a wide range of therapeutic areas and therefore represent a promising target for further investigation by DNA-encoded library screening. In pursuit of this motif, we report a novel method for the introduction of lactam-containing structures onto a DNA headpiece through the Ugi four-center three-component reaction (4C-3CR). This novel method is successful in three different approaches to give unique on-DNA lactam structures: on-DNA aldehyde coupled with isonitriles and amino acids; on-DNA isonitrile coupled with aldehydes and amino acids; and on-DNA isonitrile coupled with amines and acid aldehydes. —————————————————————————————- Speaker: Dr. Philip Clayman, Investigator at GSK – Enzyme Engineering and Biocatalysis Title: Enabling Drug Discovery and Development with Biocatalysis =========================================================== Keynote Speaker: Dr. Richmond Sarpong, Department of Chemistry, University of California–Berkeley Title: Break-it-to-Make-it Strategies for Chemical Synthesis Inspired by Complex Natural Products
Abstract: Natural products continue to inspire and serve as the basis of new medicines. They also provide intricate problems that expose limitations in the strategies and methods employed in chemical synthesis. Several strategies and methods that have been developed in our laboratory and applied to the syntheses of architecturally complex natural products will be discussed. In particular, new ways to employ the cleavage of core bonds such as C–C and C–N bonds (i.e., break-it-to-make-it strategies) to achieve skeletal editing will be presented. [1] Marth, C.J.; Gallego, G.M.; Lee, J.C.; Lebold, T.P.; Kulyk, S.; Kou, K.G.M.; Qin, J.; Lilien, R.; Sarpong, R.; Nature 2015, 528, 493. |
