Automated Parallel Synthesis Accelerates Virtual Screening Hit Discovery

Journal of the American Chemical Society, vol. 148, pp. 29908–29920

Abstract

Virtual screening (VS) is a powerful approach to exploring a vast chemical space, encompassing libraries of millions to billions of compounds. However, the low hit rates of VS require testing numerous candidates to validate true binders, followed by iterative optimization cycles, which makes experimental validation costly and time-consuming. Here, we report COMBINAUT, an automated parallel synthesis platform that generates diverse chemical scaffolds to accelerate hit validation and refinement. Using a faculty-wide collection of in-house building blocks, the system enables enumeration of over 22.9 million compounds, each designed for parallelized synthesis within 32 h using repurposed solid-phase peptide synthesis equipment. Using this platform, we performed large-scale VS targeting the allosteric pocket of the immuno-oncology target, C-C chemokine receptor 2 (CCR2). Our approach facilitated the rapid synthesis and testing of 100 VS hits spanning diverse molecular architectures. In radioligand binding assays, we successfully validated nine hits with distinct scaffolds, including completely novel CCR2 ligand chemotypes. Iterative hit-to-lead optimization using the automated workflow produced cell-active CCR2 antagonists. This work demonstrates the synergy of automated synthesis and VS, enabling the efficient exploration of chemical space and the rapid discovery of novel ligands.

Authors 10

1. Sean M. McKenna Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden Academic Centre for Drug Research

   Leiden University

   Oncode Institute

2. Martin Šícho Aachen

   Leiden University · National Infrastructure for Chemical Biology · University of Chemistry and Technology, Prague

   Affiliation as printed

   CZ-OPENSCREEN, National Infrastructure for Chemical Biology, Department of Informatics and Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague, Czech Republic

   Leiden Academic Centre for Drug Research

   Leiden University

3. Cas van der Horst Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden Academic Centre for Drug Research

   Leiden University

   Oncode Institute

4. Jesse Maasland Aachen

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research

   Leiden University

5. Edith van der Nol Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden Academic Centre for Drug Research

   Leiden University

   Oncode Institute

6. Gianluca Turco Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden Academic Centre for Drug Research

   Leiden University

   Oncode Institute

7. Andrius Bernatavicius Aachen

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research

   Leiden University

8. Gerard J. P. van Westen corresponding Aachen

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research

   Leiden University

9. Laura H. Heitman corresponding Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden Academic Centre for Drug Research

   Leiden University

   Oncode Institute

10. Sebastian J. Pomplun corresponding Aachen

    Leiden University · Oncode Institute

    Affiliation as printed

    Leiden Academic Centre for Drug Research

    Leiden University

    Oncode Institute