Arnold C. Ott Lecture: How are new drugs discovered?
Prof. Brian Shoichet
Date and TimeThursday, October 5, 2017
5:00 PM - 7:30 PM
- Kirkhof Center » RM 2250 GRAND RIVER ROOM
Prof. Brian Shoichet from the University of California, San Francisco
Thursday October 5
Reception: 5 pm
Evening Lecture: 6 pm
Location: Grand River Room, Russel H. Kirkhof Center, Allendale Campus
Title: How are new drugs discovered?
Abstract: A foundation of the modern medicine that has so successfully extended life-span and quality is the treatment of disease by drugs. I will discuss the social, economic, and technological events that have enabled the flowering of drug discovery in the last 70 years, the regulatory and technological challenges of the modern field, and the new scientific discoveries that are driving it forward.
Friday October 6th
Location: Pere Marquette Room, Russel H. Kirkhof Center, Allendale Campus
Title: Structure-based discovery for under- and over-studied GPCRs
Abstract: Receptor binding sites are evolved to recognize a few endogenous ligands, but the degeneracy of molecular recognition ensures that many other ligands and chemotypes can bind to the same site. Sometimes these non-biological molecules will confer activities that the native ligands do not.
Structure-based docking screens large compound libraries for novel molecules that physically complement a binding site, but do not resemble known ligands. When these searches are coupled to the right biological assays, they can find new molecules conferring new biology. This can happen for three reasons: targeting of an entirely new receptor, targeting of a new site on a known receptor, and occasionally targeting a known site on a well-established receptor with new biology. This will be illustrated by example with screens for new ligands that de-orphanize understudied GPCRs, like GPR68 and MRGPX2, and for ligands that target the highly studied m-opioid and D4 receptors. New opportunities arising from a huge increase in the number of readily available molecules will be considered.
Brian Shoichet received his B.Sc in Chemistry from MIT (1985). In doctoral work with Tack Kuntz (UCSF), he co-developed the first molecular docking screens, applying these to lead discovery against thymidylate synthase, a cancer target (Shoichet et al., Science 1993). As a Damon-Runyon Fellow with Brian Matthews (Institute of Molecular Biology), he used crystallography, mutagenesis, and biophysics to investigate a trade-off between enzyme activity and stability (Shoichet et al, PNAS 1995). In 1996, he joined the faculty of Northwestern University and was recruited back to UCSF in 2003, where he is a professor of Pharmaceutical Chemistry.
The Shoichet lab combines theoretical and experimental biophysical chemistry and chemoinformatics for drug discovery. The lab has published over 180 papers which have been cited over 27,000 times. Contributions include:
- Discovery of new chemotypes for the antibiotic resistance enzyme b-lactamase (Powers et al., Structure 2002).
- Discovery of a stability constraint on the evolution of drug resistance (Wang et al., J. Mol. Biol. 2002)
- Discovery of colloidal aggregation, the single largest contributor to artifacts in early drug discovery (McGovern et al., J. Med. Chem. 2002; Feng et al., Nature Chem Biol. 2008).
- New methods in computational and structure-based drug discovery (Keiser et al., Nature 2009; Lounkine et al., Nature 2012; London et al., Nature Chem. Biol. 2014).
- Application of these methods to deorphanizing the “dark-matter” of the genome (Huang et al., Nature 2015; Lansu et al., Nature Chem Biol 2017), and to the discovery of analgesics that reduce pain without reinforcing behavior (Manglik et al., Nature 2016).
Shoichet is an inventor on 12 patents and has founded three companies. He lives in Marin County, California with his wife, son, and a neurotic terrier. His mother says he is very famous.