At the American Chemical Society Fall 2020 Virtual Meeting & Expo, several Atomwise members and partners were selected to present their research and work. Learn what our Atoms have been working on below and visit Atomwise at ACS Fall 2020 Virtual Meeting & Expo for other presentation sessions.
Daniel Keedy, PhD
City University of New York
Atomwise Collaborator: Christian Laggner, PhD
Other Collaborators: Tamar Skaist, Syeda Maryam Azeem, Sakib Hossain, Kristiana Smith, Louise Dunnett, Alice Douangamath, Romain Talon, Frank von Delft
Title: Toward Inhibition of the Dynamic Enzyme PTP1B via a New Allosteric Weak Point
Division: BIOL
Abstract
PTP1B is a highly validated drug target for diabetes, cancer, and other diseases. Unfortunately, no drugs have been developed for PTP1B because its active site is charged and conserved, which limits bioavailability and selectivity for active-site binders. Allosteric inhibition offers the potential to bypass these hurdles and achieve specific inhibition of PTP1B. A recent X-ray crystallographic study of PTP1B combined high-throughput screening of small-molecule fragments and variable temperature to reveal both a broadened allosteric network spanning the enzyme’s structure and high-resolution poses for over 100 fragments bound at novel allosteric sites. Although these fragments bind at provocative allosteric sites, they are functionally benign, likely because of their very low binding affinity. The challenge remains to exploit these rich structural data to develop high-affinity, potent allosteric modulators (preferably inhibitors) of PTP1B enzyme activity. Here, we have used several structure-based approaches, including a partnership with Atomwise via the AIMS Program, to develop optimized small-molecule ligands for PTP1B that target one of these recently revealed but previously untargeted allosteric sites, and bias it toward one of an ensemble of previously observed conformations. We have identified new high-affinity binders (high nM to low µM Kd) from these efforts. Although current experiments are paused due to the COVID-19 pandemic, we will continue our efforts to characterize the functional effects of these promising new compounds via binding and activity assays, and to explore their mechanistic basis via high-throughput crystallography at room temperature as well as other structural biology techniques. Ultimately, this works sets the stage for future development of optimized PTP1B inhibitors by our group and others, and may inform future efforts to achieve allosteric control of protein function.
Speaker Presentation
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