Join the CACHE Challenges!

Calling all computational chemists and artificial intelligence (AI)-savvy scientists from academia, biotech and pharma to participate in the CACHE Challenges to predict small molecules (hits) that bind to predefined disease-associated protein targets. In 2024, Conscience became the steward for the CACHE Challenges, which were originally launched by the SGC.

Each CACHE Challenge will focus on a specific protein target of biological or pharmaceutical relevance. Participants will predict hits and CACHE will validate these hits experimentally. Each competition includes a hit-finding and a hit expansion round of prediction and experimental testing after which all data, including chemical structures, will be made publicly available without restrictions on use.

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Recent Challenges

Challenge #7

Finding Selective Inhibitors of Phosphoglycerate Kinase 2

The seventh CACHE challenge is focused on PGK2, a kinase and a potential contraceptive drug target effecting sperm bioenergetics that is being actively pursued within the Gates Foundation non-hormonal contraceptive program. This challenge is supported by unpublished data provided by program members Damian Young and Kevin MacKenzie (BCM), Neelagandan Kamariah (inStem), Levon Halabelian and Hui Peng (SGC-Toronto), and Tim Willson (SGC-UNC).

CACHE participants are tasked with identifying orthosteric inhibitors that are selective for PGK2 over its close homologue PGK1, a glycolytic enzyme with available crystal structures in the PDB. All sidechains in the ligand binding pocket are conserved except for Y242 (PGK2) vs F242 (PGK1) and A255 (PGK2) vs T255 (PGK1) at the edge of the pocket.

Figure 1: Structural chemistry of PGK1/2 inhibition. The ATP-bound structure has the PDB identifier 2X15 (a). Overview of structures (b) and ligands (c), most unpublished, that may inform the computational prediction of non-quinazoline inhibitors selective for PGK2 vs PGK1.

Available structural data include ATP-bound and ligand-bound hPGK1, ATP bound and apo mPGK2, and hPGK2 bound to two selective PGK2 quinazoline inhibitors (compound 21 and compound 47). hPGK1 bound to a selective quinazoline PGK1 inhibitor (compound 45) is also provided. Atomic coordinates and electron density files are available here.

Preliminary data on unpublished non-quinazoline ligands with some selectivity for PGK2 are shown (Figure 1c).

CACHE participants are also provided with 1388 hPGK2 hit candidates from a DNA-encoded library (DEL) screen (5 reads or more) that are not enriched in a hPGK1 screen. These compounds have not been tested off-DNA. As typical for DEL data, the signal-to-noise ratio is expected to be low and should be interpreted accordingly (ex: Montoya et al 2025).

The quinazoline series is well-advanced and will be published soon. CACHE #7 participants are therefore asked to discover SELECTIVE hPGK2 inhibitors that DO NOT contain a quinazoline.

 

 

Last date to apply is:  

Join the Challenge

Challenge #6

Finding ligands targeting the triple Tudor domain of SETDB1

The sixth CACHE challenge is focused on SETDB1, a multi domain protein involved in epigenetic mechanisms and an immuno-oncology target. Participants are asked to find molecules occupying one or multiple subcavities of the histone binding groove of the SETDB1 triple Tudor domain (TTD). A few ligands (PDB codes 7CJT, 8UWP, 6AU3) occupy one or two of three subcavities that accommodate methylated or acetylated lysine sidechains, as shown in this structure overview.

 

Last date to apply is:  

Challenge #5

Predicting Novel MCHR1 Antagonists

The fifth CACHE challenge is focused on MCHR1, a G-Protein coupled receptor linked to obesity, sleep disorders and with potential roles in depression and anxiety disorders.

CACHE participants are asked to predict chemically novel antagonists for MCHR1.

More details are shared in the data package on the Challenge #5 page.  

 

Last date to apply is:  

Challenge #4

Finding ligands targeting the TKB domain of CBLB

This CACHE challenge is focused on the TKB domain of CBLB, an E3 ubiquitin-protein ligase with hundreds of compounds reported in the patent literature from multiple organizations, all chemically related. CACHE participants are asked to predict compounds with new scaffolds.

More details are shared in the data package on the Challenge #4 page.

Last date to apply is:  

Challenge #3

Finding ligands targeting the macrodomain of SARS-CoV-2 Nsp3

Predict ligands that bind to the ADPr site of SARS-CoV-2 Nsp3 macrodomain (Mac1). 

Mac1 interferes with the immune response to viral infection and is a valid target against SARS-CoV.

More details are shared in the data package on the Challenge #3 page.

 

Last date to apply is:  

Challenge #2

FINDING LIGANDS TARGETING THE CONSERVED RNA BINDING SITE OF SARS-CoV-2 NSP13

Finding ligands targeting the conserved RNA binding site of SARS-CoV-2 NSP13.

The RNA-binding site of NSP13 is the most conserved site in SARS-CoV-2 and across coronaviruses. The underlying selective pressure is expected to apply to future coronavirus outbreaks and drugs binding this site should be effective against future pandemic threats.

More details are shared in the data package on the Challenge #2 page.

Last date to apply is:  

Challenge #1

PREDICT HITS FOR THE WDR DOMAIN OF LRRK2

Predict hits for the WD40 repeat (WDR) domain of LRRK2, a Parkinson's Disease target.

LRRK2 is the most commonly mutated gene in familial Parkinson's Disease. 

More details are shared in the data package on the Challenge #1 page.

Last date to apply is: