Discovery of Inhibitors of WDR Domain-Containing Proteins using a Deep Convolutional Neural Network

April 01, 2021
Events, ACS2021

At the American Chemical Society Spring 2021 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 Spring 2021 Virtual Meeting & Expo for other presentation sessions. 


Tigran Abramyan, PhDTigran Abramyan, PhD 

Title: Discovery of Inhibitors of WDR Domain-Containing Proteins using a Deep Convolutional Neural Network

Division: MEDI



Authors: Tigran M. Abramyan (1), Irene Chau (2), Fengling Li (2), Sumera Perveen (2),
Albina Bolotokova (2), Levon Halabelian (2), Ashley Hutchinson (2), Peter Loppnau (2), Santha Santhakumar (2), Almagul Seitova (2), Hong Zeng (2), Suzanne Ackloo (2), Niel Henriksen (1), Terry O'Brien (1), Denzil Bernard (1), Jon Sorenson (1), Dalia Barsyte-Lovejoy (2), Peter Brown (2), Masoud Vedadi (2), Cheryl Arrowsmith (2), Matthieu Schapira (2)

1. Atomwise Inc, San Francisco, CA, United States.
2. Structural Genomics Consortium, Toronto, ON, Canada.



WD40 repeats (or WDR domains) are some of the most abundant protein interaction domains in the human proteome, representing essential subunits of multiprotein complexes involved in a wide variety of cellular processes, ranging from cell signaling, growth, and division to protein degradation. The domain has a beta-propeller structure with an overall doughnut shape. The central pore of the domain is typically involved in interactions with peptide regions of key interaction partner proteins. While these pores of some WDR domains could be druggable pockets, often they can be challenging to target with small drug-like molecules due to their relatively shallow and solvent exposed nature. Here, using the AtomNet® model, a deep convolutional neural network for structure-based drug discovery, we screened billions of compounds against WDR domain-containing proteins, implicated in various illnesses such as heart disease and cancer. We identified several small drug-like molecules exhibiting micromolar binding affinities validated by differential scanning fluorimetry and surface plasmon resonance experiments. This effort will support SGC’s Target 2035 initiative to discover molecular probes for nearly all human proteins.


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