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

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 × 1012 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.

Graphical abstract: A vending machine for drug-like molecules – automated synthesis of virtual screening hits

Supplementary files

Article information

Article type
Edge Article
Submitted
17 Sep 2022
Accepted
27 Oct 2022
First published
28 Oct 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2022, Advance Article

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

A. E. McMillan, W. W. X. Wu, P. L. Nichols, B. M. Wanner and J. W. Bode, Chem. Sci., 2022, Advance Article , DOI: 10.1039/D2SC05182F

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