A vending machine for drug-like molecules - automated synthesis of virtual screening hits

• Published in: Chemical science (Cambridge) Vol. 13; no. 48; pp. 14292 - 14299
• Main Authors: McMillan, Angus E, Wu, Wilson W. X, Nichols, Paula L, Wanner, Benedikt M, Bode, Jeffrey W
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 14.12.2022; The Royal Society of Chemistry
• Subjects: Aldehydes; Amines; Automation; Chemical synthesis; Chemistry; Commercial buildings; Consoles; Digital libraries; Screening; Vending machines; Virtual libraries
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d2sc05182f

As a result of high false positive rates in virtual screening campaigns, prospective hits must be synthesised for validation. When done manually, this is a time consuming and laborious process. Large "on-demand" virtual libraries (>7 × 10 12 members), suitable for preparation using capsule-based automated synthesis and commercial building blocks, were evaluated to determine their structural novelty. One sub-library, constructed from iSnAP capsules, aldehydes and amines, contains unique scaffolds with drug-like physicochemical properties. Virtual screening hits from this iSnAP library were prepared in an automated fashion for evaluation against Aedes aegypti and Phytophthora infestans . In comparison to manual workflows, this approach provided a 10-fold improvement in user efficiency. A streamlined method of relative stereochemical assignment was also devised to augment the rapid synthesis. User efficiency was further improved to 100-fold by downscaling and parallelising capsule-based chemistry on 96-well plates equipped with filter bases. This work demonstrates that automated synthesis consoles can enable the rapid and reliable preparation of attractive virtual screening hits from large virtual libraries. A compact and operationally simple automation technology can prepare virtual screening hits from a large on-demand library of drug-like molecules.