Small molecule high throughput screening (HTS) is an industrial-like operation to identify novel entry points into drug discovery programs. In this article we discuss the functions, requirements and components of an HTS informatics infrastructure from the perspective of the end user of the data and the ultimate goal of identifying chemically tractable hits suitable for further optimization. We discuss in detail the operational / transactional informatics -systems and business processes, including chemical compound registry, inventory logistics, data management, and integration of these operational informatics systems with HTS instrumentation and robotics. We then describe HTS data analysis and discovery informatics. We review statistical methods practiced to evaluate assay stability and data quality, data normalization, hit identification and methods to correct systematic errors. Cheminformatics is required to comprehend HTS results in the context of chemical structures. We describe basic concepts, common methods and tools for chemical HTS data mining and modeling, identifying and visualizing structure-activity relationships (SAR), screening follow-up, and library design considerations. Significant additional informatics requirements are posed by high-content image based screening. We discuss both operational informatics and data analysis challenges followed by a brief summary and outlook of HTS informatics in the context of global discovery and drug informatics.
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