Following the Rabbit into Chemical Space

Dr. Brian K. Shoichet, PhD
University of California, San Francisco 

https://utoronto.zoom.us/j/86086638773

Meeting ID: 860 8663 8773

Passcode: 484696

Structure-based docking can be used to screen compound libraries for novel ligands. Recently, docking libraries  have expanded from three million “in-stock” to over four billion make-on-demand (“tangible”) molecules. Docking these new libraries versus the dopamine, melatonin, and 2 receptors have revealed novel scaffolds with nM and sub-nM potencies directly from the docking. I will discuss recent applications to the alpha2a-adrenergic, serotonin, and cannabinoid receptors, and the serotonin transporter, where in vivo active leads have been developed for analgesia, depression, and opioid withdrawal. 

Methods questions will also be considered: the effect of bias toward bio-like molecules in the virtual libraries, how and if docking score improves as the libraries grow, how number tested affects the quality of the experimental actives, and whether we have reached a plateau in the results we can expect from large library docking, or if bigger remains better. 

Biography 

Brian Shoichet received a B.Sc. in Chemistry and a B.Sc. in History in 1985, from MIT. MIT appears to have no record of this. He received his Ph.D. for work with Tack Kuntz on molecular docking in 1991, from UCSF. Shoichet’s postdoctoral research was largely experimental, focusing on protein structure and stability with Brian Matthews at the Institute of Molecular Biology in Eugene, Oregon, as a Damon Runyon Fellow. Colleagues from Eugene have only sketchy 

memories of his time there. One recalls, “He seemed to travel a lot.” Matthews himself was unavailable for comment. Shoichet joined the faculty at Northwestern University in the Dept.of Molecular Pharmacology & Biological Chemistry as an Assistant Professor in 1996. No record of this Department’s existence can be found outside of one locked filing cabinet in Gene Silinsky’s office. Silinsky was unavailable for comment. In a fit of absent-mindedness, Shoichet was promoted to a tenured Associate Professor in 2002, only one year after his younger sister, Molly Shoichet, received tenure at the University of Toronto. Shoichet denies any sensitivity around this issue. Around that time he was recruited back to UCSF, where he is now a Professor in the Department of Pharmaceutical Chemistry. We confused him with Kevan Shokat, admits a member of the recruiting committee at UCSF. A charismatic speaker, he is recalled as giving ‘the best talk at the worst Keystone Conference I ever attended,’ by a senior NIH Program Officer. 

Research in the Shoichet Lab seeks to bring chemical reagents to biology, combining computational simulation and experiment. An unanticipated observation emerging from the theory/experiment cycle was the colloidal aggregation of organic molecules. This phenomenon has great effects in early and late drug discovery, and we continue to investigate it. More broadly, we adopt a protein-centric approach that seeks new ligands to complement protein structures. This involves new docking methods, model experimental systems to test them. Using a ligand-centric approach, we seek new targets for established drugs and reagents. Whereas this lacks the physical foundation of the structure-based research program, it returns to an older, pharmacological view of biological relationships, bringing to it a quantitative model. A focus for both approaches is ligand discovery against G Protein-Coupled Receptors (GPCRs). 

Hosted by Dr. Molly Shoichet Snacks and refreshments will be served.