High-Throughput Screening

Introduction & rationale

• Definition — High-throughput screening (HTS) is an automated, microprocessor-controlled robotic process that screens very large compound libraries against a validated biological target — a synergy of chemistry, biology, engineering and informatics that replaced the older slow, manual screening of compounds.
• Throughput — HTS screens 50,000–100,000 compounds per week; ultra-HTS (uHTS) screens 10,000–100,000 compounds within 24 h. It is fed by high-throughput (combinatorial) synthesis of the test compounds.
• Why HTS replaced conventional screening — conventional discovery was a slow, tedious, manual process demanding huge manpower, time and money, with test-tube chemistry risking loss of precious samples and lacking sensitivity. A rising disease burden (cardiovascular, diabetes, immune, infectious) and treatment failure demand faster delivery of better compounds.
• Pace contrast — traditional techniques took nearly half a century to exploit the cholesterol pathway and develop statins; by contrast in-silico modelling + HTS + genomic/proteomic databases enabled Herceptin (trastuzumab) against the HER-2 receptor within ~3 years.
• Enabling advances — the technologies that cumulatively raised lead-generation speed are combinatorial chemistry, biochemical assays, genomics, proteomics, miniaturisation, automation, robotics and computerisation.
• Bottleneck shift — the genuine bottleneck has moved from drug discovery to drug development — combinatorial chemistry now yields thousands of leads/year (vs ~100 a decade earlier), so the preclinical toxicity, bioavailability and pharmacokinetic battery becomes rate-limiting; DMPK prioritisation of leads is therefore critical in the hit-to-lead phase.