A vending machine for drug-like molecules – automated synthesis of virtual screening hits. Issue 48 (24th November 2022)

• Record Type: Journal Article
• Authors: McMillan, Angus E.; Wu, Wilson W. X.; Nichols, Paula L.; Wanner, Benedikt M.; Bode, Jeffrey W.
• Is Part Of: Chemical science. Volume 13:Issue 48(2022)
• Page Start: 14292
• Page End: 14299
• Publication Date: 2022-11-24
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d2sc05182f
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : A compact and operationally simple automation technology can prepare virtual screening hits from a large on-demand library of drug-like molecules. Abstract : 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.