CACHE Benchmarking Event 1

CACHE Competition 1 participants will be predicting small molecules (hits) that bind to LRRK2's WD40 repeat (WDR) domain. The competition will officially start on 1st February 2022 and lasts for ~20 months. The goal is to make all data, including chemical structures, publicly available without restrictions on use.

HOW IT WORKS

Each challenge will focus on a new protein target representing one of five possible challenges in hit-finding, based on the type of data available:

Protein structure in complex with a small molecule, some structure-activity relationship (SAR)
Protein structure in complex with a small molecule, no SAR
Apo protein structure
No experimentally determined protein structure, some SAR
No experimentally determined protein structure, no SAR

For each challenge, participants will be invited to use their computational methods to find hits (drug-like molecules) for a protein target selected by CACHE. CACHE will procure the molecules from commercial vendors and test them experimentally with two rigorous binding assays. Compounds from de novo design methods will be procured by participants [details]. The purity and solubility of active molecules will also be evaluated experimentally. CACHE will provide each participant with the experimental protein binding data for their prediction. Using this knowledge, participants may predict a second round of molecules that will be experimentally tested by CACHE. Additionally, the structures of all selected molecules, but not their activity, will be made available to all participants who will be asked to use their computational method to identify hits. The final evaluation process will incorporate:

experimental hit rate
affinity and physico-chemical properties of the hits from a participant’s selection
rank-ordering of compounds pooled from all participants.
A panel of experienced medicinal chemists will also comment on the hits.

Participants will be asked to disclose their approaches in sufficient detail to enable an expert in the area to understand the methodology while computational algorithms can remain proprietary. At the end of the competition, all chemical structures and associated activity from all participants will be disclosed to the public. Participants who had elected to be anonymous will have the choice to disclose their identity at any time.

Additional information