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 three 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.

计算化学的一个理想目标是预测任何蛋白质的有效和类似药物的结合剂，以便仅合成那些结合的蛋白质。在此路线图中，我们描述了计算命中发现实验的关键评估 (CACHE) 的启动，这是一个公共基准测试项目，用于通过预测和实验测试的循环来比较和改进小分子命中发现算法。参与者将预测代表不同预测情景的新的和生物学相关的蛋白质靶标的小分子结合剂。预测的化合物将在实验中心进行严格测试，所有预测的结合剂以及所有实验筛选数据，包括实验测试化合物的化学结构，都将公开提供，不受任何知识产权限制。将评估、比较并公开发布一系列计算方法寻找新型结合剂的能力。CACHE 每年将推出三个新的基准测试活动。结果将是更好的预测方法、对基础生物学或药物发现具有重要意义的靶蛋白的新小分子结合剂，以及实现 Target 2035 目标的重大技术步骤，Target 2035 是一项为所有人类蛋白质确定药理学探针的全球倡议。