Computational tools for structure-based drug design (SBDD) are widely used in drug discovery and can provide valuable insights to advance projects in an efficient and cost-effective manner. However, despite the importance of SBDD to the field, the underlying methodologies and techniques have many limitations. In particular, binding pose and activity predictions (P-AP) are still not consistently reliable. We strongly believe that a limiting factor is the lack of a widely accepted and established community benchmarking process that independently assesses the performance and drives the development of methods, similar to the CASP benchmarking challenge for protein structure prediction. Here, we provide an overview of P-AP, unblinded benchmarking data sets, and blinded benchmarking initiatives (concluded and ongoing) and offer a perspective on learnings and the future of the field. To accelerate a breakthrough on the development of novel P-AP methods, it is necessary for the community to establish and support a long-term benchmark challenge that provides nonbiased training/test/validation sets, a systematic independent validation, and a forum for scientific discussions.

Bayer AG Drug Discovery Sciences 13353 Berlin Germany

Computation Relay Therapeutics Cambridge Massachusetts 02141 United States

Departments of Pharmaceutical Sciences and Chemistry University of California Irvine Irvine California 92697 United States

F Hoffmann La Roche Ltd Pharma Research and Early Development Basel 4070 Switzerland

Global Discovery Chemistry Novartis Pharma AG Basel 4002 Switzerland

In Silico Discovery Therapeutics Discovery Johnson and Johnson Innovative Medicine San Diego California 92121 United States

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague 16000 Czech Republic

Medicinal Chemistry Boehringer Ingelheim Pharma GmbH and Co KG Biberach an der Riss 88397 Germany

Medicinal Chemistry Research and Early Development Respiratory and Immunology BioPharmaceuticals R and D AstraZeneca 43183 Gothenburg Sweden

Memorial Sloan Kettering Cancer Center New York New York 10065 United States

Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego La Jolla California 92093 0736 United States

Structural Genomics Consortium and Department of Pharmacology and Toxicology University of Toronto Toronto Ontario M5G 1L7 Canada

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