Hongwu Wang, a principal scientist from Merck with 20 years of experience in the pharmaceutical industry, delivered a presentation on high throughput screening (HTS) in the small molecule area. Wang began by discussing the critical role of HTS in lead discovery for various projects, noting that despite its widespread use, only 21% of clinical candidates were sourced from random screening. He mentioned that an analysis at Merck revealed that 42% of preclinical candidates originated from internal screening, with 16% from hybridisation of known series.
Wang discussed the implementation of a diversity screening strategy at Merck, which involved screening diverse subsets of their full compound collection. This strategy included the use of virtual screening to develop project-specific sites and augment the diversity library. He emphasised the importance of higher data quality in primary screening, achieved by screening in triplicate. Additionally, a focused training workflow protocol was implemented to build machine learning models using HTS data, aiding in the identification of new lead series.
The presentation detailed the definition of a diverse screening library, which utilised 2D clustering and an MPO score to enrich 3D shape and biological diversity. Wang also described the adoption of a progressive plating scheme, ensuring high-quality samples and updating the diversity deck every other year. He outlined the typical HTS hit finding funnel at Merck, which included primary screening, dose response, counter screening, and orthogonal screening to ensure genuine hits.
Wang highlighted the use of project-specific virtual screening and specialty collections, such as covalent modifiers, FDA-approved drugs, and GPCR collections. He also mentioned the design of an External_50k deck for external collaborations. The presentation concluded with an analysis of HTS outcomes, revealing that validated hits were delivered for two-thirds of small molecule HTS screens. Wang ended by acknowledging areas for improvement, particularly in transcription factors and PPI targets.
