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To be eligible for consideration this Application form must be submitted on cache-challenge.org by 23:59 CET on May 1st 2023.
Please note that by submitting this Application and, if accepted for participation, by making one or more Submissions to this CACHE Challenge, you are agreeing on behalf of yourself and your organization to the CACHE Terms of Participation, found here: https://cache-challenge.org/CACHE_Terms_of_Participation.pdf.
Please fill in all fields in this form in order to be eligible to participate.
APPLICATIONS REVIEW:
Applications will be pre-screened at CACHE to ensure that the Applicant research group or company has published in the field or otherwise has appropriate qualifications. Applications will then go through a double-blind peer-review process where the Computational Approach Description(s) submitted below will be available to the reviewers. Each Applicant that passes the pre-screen stage will be asked to review the quality of the Computational Approach from five other Applicants (without identifying Applicants) and to verify that the Computational Approach Descriptions are sufficiently detailed that an expert in the field could readily understand the Applicants’ prediction strategies. Applications that pass the double-blind peer-review stage will be reviewed by an independent committee convened by CACHE that will select up to 25 Applicants to participate and make submissions of binding predictions to this CACHE Challenge.1 All selected Participants will be anonymized.
1. CACHE has no obligation to accept any particular Application but, resources permitting, will strive to accept all Applications with viable Computational Approach Descriptions and appropriate Applicant qualifications, as determined by CACHE in its discretion.
THE CHALLENGE:
The Challenge will be composed of three steps:
[1] hit identification: Participants will select or design up to 100 hit candidates that bind to the closed conformation of the CBLB TKB domain with novel chemical templates and KD below 30 micromolar. Compounds should target the site exploited by the ligand in PDB code 8GCY.
[2] virtual screening of merged selections: Participants will receive a file with the chemical structures of all hit candidates selected by all Participants in step [1], and will predict which compounds are active
[3] hit optimization: Participants who have at least one hit-candidate from step [1] with novel chemical scaffold experimentally validated and KD < 30 µM will select or design up to 50 follow-up compounds
RELEASING THE DATA:
All Computational Approach Descriptions associated with a particular step of the challenge ([1] hit identification; [2] virtual screening of merged selections; [3] hit optimization) will be publicly released immediately after all predictions for this particular step are submitted. For steps [1] and [3] of the challenge, all experimental data on all compounds from all Participants, but without the structure of the compounds, will be publicly released immediately after the data was generated for all Participants. Participants will be able to link the data to compound structures, but only for their compounds. Molecular weight and cLogP ranges of compounds will be publicly released. Immediately after all Participants have submitted their prediction for step [2] of the challenge and the activity of all compounds has been determined experimentally, the status (“active” or not) predicted by all Participants will be compared with the experimental activity and publicly released. Compound structures will remain undisclosed. All data and all compound structures will be publicly released at the end of the challenge, at least three months after the experimental data are shared with the relevant Participant. At the end of the competition, the three top-performing Participants will be de-anonymized and their identities publicly released, as well as all Participants that request to be publicly identified, and Participants that withdrew before the end of the competition. -- Please note that by entering this competition, pursuant to the CACHE Terms of Participation of this CACHE Challenge (see above), you and your organization are agreeing that none of the compounds submitted to CACHE will be patented by you or your organization and are instead intended as public domain resources. Your algorithms, software code, and reproducible workflows, including any improvements you make to them through participation in this CACHE Challenge, are your Intellectual Property and no licenses or rights are granted by you in them (unless you have made them open source and indicated as such below).
CACHE will cover 50% of the costs of testing compounds experimentally (including attempts to co-crystallize the best compounds by the team at the SGC that solved structure 8GCY). In addition, CACHE will cover 50% of the costs of procuring the compounds for academics and companies with less than 20 employees, and 75% of the costs for participants who make their software opensource.
The information in this section will be maintained confidential unless you click otherwise below, or are in the top three performing Participant’s in this CACHE Challenge.
Details of the corresponding applicant (to whom emails will be sent):
If your application is accepted:
You will have two months starting June 1st 2023, with a Submission deadline August 1st 2023, to specify 100 compounds predicted to bind to the closed conformation of the CBLB TKB domain with novel chemical templates and KD below 30 micromolar. Compounds should be commercially available at modest cost. We favor the Enamine Real Database catalog, subsets of which may be downloaded from http://cache.docking.org/ or obtained directly from Enamine. Please provide SMILES and purchasing information for each compound (Enamine ID, etc). CACHE will purchase your selected compounds (with the usual caveats about make-on-demand compounds), test them experimentally (see below) and send all data back to you, including the KD of active molecules measured by SPR by February 1st 2024. To save costs, we will purchase molecules without stereochemical resolution, as they are generally cheaper. We will attempt to purchase the lowest cost form of the compound available, requesting a salt form for solubility if available, unless otherwise requested. In addition to submitting their predictions by August 1st 2023, Participants using de novo design approaches will be responsible for having their predicted compounds and associated analytical spectra showing >95% purity received at CACHE by November 1st 2023. CACHE may, upon reasonable request, reimburse the cost of synthesis up to US$1,000 per compound received before this deadline and to a maximum of US$5,000 total per participating group. Please obtain approval from us before incurring costs you wish to be reimbursed by emailing to cache@thesgc.org.
This section will be used for double-blind peer-review and will be disclosed on cache-challenge.org anonymously (except as described above) after all participants have submitted their first compound selection:
By September 1st 2023, barring unforeseen circumstances, you will receive an SDF file with the 2D structure of all compounds selected by all Participants at the hit identification phase, but without any experimental data. You will be asked to predict actives among these compounds by November 1st 2023.
This section will be used for double-blind peer-review and will be disclosed on cache-challenge.org anonymously (except as described above) after all merged selection participants have submitted their merged selection:
By February 1st 2024, barring unforeseen circumstances, you will have received all experimental data for the compounds that you selected that were successfully delivered to CACHE. From among the hits (KD < 30 µM) that emerge from your work, you will be asked to select by April 1st 2024 an additional 50 compounds from Enamine to explore the structure-activity relationship of these experimental hits. Your file should contain the Enamine catalog numbers and SMILES string of each compound. CACHE will purchase as many of your selected compounds as can be made economically by parallel synthesis at Enamine, test them experimentally, measure the solubility and purity of the highest affinity hits, and send all data back to you, including the KD of active molecules measured by SPR by October 1st 2024.
If this second selection is not from the Enamine Real Database, participants will be responsible for synthesis and for having the compounds and associated analytical spectra showing >95% purity received at CACHE by July 1st 2024. CACHE may, upon reasonable request, reimburse the cost of synthesis up to US$1,000 per compound received before this deadline and to a maximum of US$2,500 total per participating group. Please obtain approval from us before incurring costs you wish to be reimbursed by emailing to cache@thesgc.org.
This section will be used for double-blind peer-review and will be disclosed on cache-challenge.org anonymously (except as described above) after all hit-optimization participants have submitted their selection of optimized compounds
On January 1st 2025, barring unforeseen circumstances, CACHE will publicly release the anonymized list of participants and their origin (academia, biotech, pharma etc.). As described above, Participant identity will be de-anonymized if they are a top three performer or have consented to release of their identity above. Information about a Participant’s software and/or reproducible workflows will be released if the Participant has consented above. For all Participants the following will be released:
Methods will be evaluated and ranked using a traffic-light scoring scheme detailed in Ackloo, S., et al. Nat Rev Chem 6, 287-296 (2022).
As noted above, please note that by submitting this Application and, if accepted for participation, by making one or more Submissions to this CACHE Challenge, you are agreeing on behalf of yourself and your organization to the CACHE Terms of Participation, found here: CACHE_Terms_of_Participation.
