CACHE Challenge #1 - Preliminary Experimental Validation

Here are the preliminary results from the experimental validation of compounds from the first round of selections for CACHE challenge #1. 
 

THE CHALLENGE

  • CACHE participants were asked to use their computational methods to predict ligands binding the central cavity of the WDR domain of LRRK2. There is so far no known molecule for this binding site. See details.
  • After a double-blind peer review where each applicant reviewed 5 applications, 23 participants joined the challenge, representing a diverse array of physics-based and AI computational methods.
  • Participants collectively selected 1955 compounds (no more than 100 compounds per participant) that we ordered and received from Enamine.
  • All experimental data, the structure of the compounds and their associated computational methods will be publicly released at the end of this Challenge.

EXPERIMENTAL VALIDATION

  • Compounds were first screened at 50 μM and 100 μM in a surface plasmon resonance (SPR) binding assay where biotinylated LRRK2-WDR was captured on a streptavidin chip. 
  • >200 compounds with a binding signal between 50% and 200% of the expected value were cherry picked for dose-response experiment in the same assay.
  • 73 compounds from 18 participants produced a dose response and measurable KD below 150 μM and were selected for hit expansion, where participants can select up to 50 follow-up compounds for experimental characterization.
  • The hit expansion round will be critical to build confidence in these 73 hit candidates. We expect that progressable hits will produce a clear structure-activity relationship (SAR).

Figure showing SPR data

Figure 1: Primary screen by SPR.​

 

Some of the predicted molecules produced promising data across multiple assays. We hope the hit-expansion round will generate convincing SAR.

 

Figure of experimental data for compound X

Figure 2: Multiple assay data for example compound X.

 

 

Figure of experimental data for compound Y

Figure 3: Multiple assay data for example compound Y.

 

Download a pdf summary of the preliminary results here.

 

ACKNOWLEDGEMENTS

CACHE #1 Experimental Platform, Structural Genomics Consortium, University of Toronto

Matthieu Schapira Pegah Ghiabi
Fengling Li Elisa Gibson
Suzanne Ackloo Carla Kharadjian
Sumera Perveen Almagul Seitova
Irene Chau Helen Li
Levon Halabelian Maria Kutera
Serah Kimani Albina Bolotokova
Shabbir Ahmad Rachel Harding

 

Logos of supporting partners