To be eligible for consideration this Application form must be sent by email to [email protected] latest on January 31st 2022.
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 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 only the Computational Approach Description(s) submitted below will be available to the reviewer. Each Applicant that passes the pre-screen stage will be asked to be a reviewer in the double-blind peer-review process. The Applicant will be asked to review the Computational Approach Descriptions from five other Applicants (without any identifying information about the other 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 (answer: yes/no + <100 words justification). 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. 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. The experimental data pertaining to a Participant’s submitted compounds will be shared with the Participant before public release. All compound structures, experimental data, and Computational Approach Descriptions will be publicly released at the end of the competition, but CACHE will refrain from releasing the experimental data on a Participant’s predictions until at least 3 months after the experimental data are shared with the relevant Participant.
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.
Please note that by entering this competition, pursuant to the CACHE Terms of Participation (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).
There are no fees associated with participating in this particular CACHE Challenge.
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 March 1st 2022, with a Submission deadline May 1st 2022, to specify 100 compounds predicted to bind the central cavity of the donut-shaped WDR domain of LRRK2 [PDB code 6DLO]. Compounds should be commercially available at modest cost. We favor the Enamine Real Database (via ZINC) 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 (ZINC ID, 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 November 1st 2022. To save costs, we will purchase “flat” 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 May 1st 2022, 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 August 1st 2022. CACHE may, upon reasonable request, reimburse the cost of synthesis up to US$2,000 per compound received before this deadline and to a maximum of US$10,000 total per participating group. Please obtain approval from us before incurring costs you wish to be reimbursed by emailing to [email protected].
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 June 1st 2022, 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 August 1st 2022.
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 November 1st 2022, 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 < 100 µM) that emerge from your work, you will be asked to select by January 1st 2023 an additional 100 compounds from http://cache.docking.org/ to explore the structure-activity relationship of these experimental hits. Your file should contain the ZINC/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 July 1st 2023.
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 April 1st 2023. CACHE may, upon reasonable request, reimburse the cost of synthesis up to US$2,000 per compound received before this deadline and to a maximum of US$10,000 total per participating group. Please obtain approval from us before incurring costs you wish to be reimbursed by emailing to [email protected].
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 October 1st 2023, 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: Computational Method Description(s) Structures of selected compounds and associated experimental data Virtual screening of merged selection Methods will be evaluated and ranked using a traffic-light scoring scheme detailed in https://doi.org/10.33774/chemrxiv-2021-rzq4n 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: https://cache-challenge.org/CACHE_Terms_of_Participation.pdf.
