Distinguished Seminar Series: Shoichet to outline impact of docking library on May 10


Published May 4, 2021

“The libraries continue to grow, now approaching 1.5 billion and expected to exceed 4 billion by end of this year. To accommodate this, the underlying docking method has been sped up by about 10-fold.”
Brian Shoichet, PhD.

The 2020-21 University at Buffalo Clinical and Translational Science Institute (CTSI) Distinguished Seminar Series season has featured top experts speaking on topics of health disparities and the COVID-19 pandemic. Now, the series concludes for the spring semester on May 10 with internationally renowned researcher Brian Shoichet, PhD, Professor, Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco.

Shoichet’s talk is titled “Virtual Screens of Billion Compound Libraries for Novel Ligands With New Pharmacology.” Scheduled from 4 to 5 p.m. on Monday, May 10, the presentation will happen online via Zoom. Register now on the CTSI website.

A goal of the Shoichet lab is to discover chemical reagents that can illuminate biological problems. A longstanding effort to do so is by exploiting protein structures to predict new reagents and therapeutic leads (structure-based ligand discovery). The lab seeks novel chemotypes by docking screens compound libraries for molecules that complement the structures of protein targets. Often, these new chemotypes can confer new biology.

In 2019, the libraries expanded from 3 million “off-the-shelf” to over 1 billion “make-on-demand” molecules. The lab first explored the pragmatism of such ultra-large, virtual libraries in prospective campaigns against β-lactamase and the dopamine D4 receptor, where new docking hits were tested functionally and, were possible, by crystallography. By testing over 500 new-to-the-planet molecules, researchers could correlate docking score and likelihood of binding for the first time. Subsequent studies were expanded to discover biologically active lead molecules for the melatonin receptors, the 5HT2a receptor, and the sigma2 receptor.

The initial unveiling of this virtual library of drug-like compounds for researchers to mine for tomorrow’s cures drew headlines around the world. As Science framed the finding, “It’s the drug discovery equivalent of looking for a book on Amazon versus at your local library. Researchers have scanned a chemical database … to identify a handful of new compounds that could serve as starting points for novel antibiotics and antipsychotic medications.”

In advance of his May 10 presentation, Shoichet told the CTSI how things have changed since the launch of the library in 2019.

“The libraries continue to grow, now approaching 1.5 billion and expected to exceed 4 billion by end of this year,” Shoichet says. “To accommodate this, the underlying docking method has been sped up by about 10-fold. Many other groups have jumped on this idea, both in industry and in academia, with other groups publishing favorable results.”

Shoichet adds that “one of the first demonstrations of the power of the new libraries was in collaboration with [UB CTSI Workforce Development Core Director] Margarita Dubocovich, PhD, applying them to discover novel chemotypes with unexpected pharmacology against the melatonin receptors, in work that was published in Nature last year.”

His upcoming talk will outline some of the discoveries the database has led to since its launch. In addition, the virtual seminar will feature a discussion of opportunities and challenges from this 100-fold increase in community-accessible chemical space.

“It’s an amazing leap for scientists who look at small molecules,” explained Shoichet in 2019. “The number of molecules we have access to is almost unbounded now. The only thing limiting us is our ability to enumerate molecules and then search them.”

For questions about the CTSI Distinguished Seminar Series, contact scholar1@buffalo.edu or (716) 829-4718.