CACHE (Critical Assessment of Computational Hit-finding Experiments): A public-private partnership benchmarking initiative to enable the development of computational methods for hit-finding

Abstract

One aspirational goal of computational chemistry is to predict potent and drug-like binders for any protein, such that only those that bind are synthesized. In this Roadmap, we describe the launch of Critical Assessment of Computational Hit-finding Experiments (CACHE), a public benchmarking project to compare and improve small molecule hit-finding algorithms through cycles of prediction and experimental testing. Participants will predict small molecule binders for new and biologically relevant protein targets representing different prediction scenarios. Predicted compounds will be tested rigorously in an experimental hub, and all predicted binders as well as all experimental screening data, including the chemical structures of experimentally tested compounds, will be made publicly available, and not subject to any intellectual property restrictions. The ability of a range of computational approaches to find novel binders will be evaluated, compared, and openly published. CACHE will launch 3 new benchmarking exercises every year. The outcomes will be better prediction methods, new small molecule binders for target proteins of importance for fundamental biology or drug discovery, and a major technological step towards achieving the goal of Target 2035, a global initiative to identify pharmacological probes for all human proteins.

Fig. 1.. CACHE challenge workflow.

1. Hit-finding challenges: CACHE presents a variety of hit-finding challenges to the community, including assessment criteria. 2. Virtual libraries: CACHE will establish and host two virtual libraries; a make-on-demand library (REAL, ZINC20) and a library comprising compounds synthetically accessible by chemists in academia or industry (bespoke chemistry). 3. Participants predict chemical matter & CACHE experimentally tests compounds: Each participant will have opportunity to make two cycles of predictions per round. CACHE will procure and assay the predicted compounds. At this stage, structures of compounds will be made available to all participants, but screening data will be provided only to the specific participant and competition management, in order to serve as a starting point for an additional cycle of predictions. 4. Compounds, data placed in the public domain: Once the second cycle is complete, the data package, including all structures and screening data, as well as an assessment of each compound, will be made available to all, without restriction.

Fig. 2.. Target selection consideration and classes of CACHE challenges.

A. Targets will be selected from a long list of proteins that represent a range of scenarios of varying technical difficulty, are experimentally enabled (for example, there must be a robust binding assay) and, where possible, represent opportunities to make new biological or medical discoveries. Funders can prioritize targets within each challenge. B. The five potential hit-finding scenarios that address key technical questions in computational chemistry. SMOL: small molecule.

Fig. 3.. The timelines of challenge activities.

After reviewing the Letters of Intent (LOI), each complete challenge round will take ~18 months, with the various stages outlined.

Fig. 4.. CACHE governance.

CACHE will be structured as an independent, not-for-profit entity. The CACHE governance will include a Governing Board constituted by funders (Members) and two independent Members selected with input from the scientific community; an External Scientific Advisory Board; and a Secretariat that will oversee day-to-day operations. The Governing Board will create three scientific committees: the Target Selection Committee will select protein targets (with final decision impacted by the Governing Board); the Virtual Libraries Committee will define the virtual chemistry libraries to be screened; and the Hit Evaluation Committee will create the metrics of success and assess performance against the metrics. Funders that do not wish to play an active role in governance can nominate targets for consideration by the Target Selection Committee.