Automated Parallel Synthesis Accelerates Virtual Screening Hit Discovery

ChemRxiv

Abstract

Virtual screening (VS) is a powerful approach to explore 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, making 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 1-32 hours using repurposed solid-phase peptide synthesis equipment. Using this platform, we performed large-scale virtual screening 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 virtual screening 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 efficient exploration of chemical space and rapid discovery of novel ligands.

Authors 9

1. Sean M. McKenna Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden University

   Oncode Institute

2. Martin Šícho Aachen

   Leiden University · University of Chemistry and Technology, Prague

   Affiliation as printed

   Faculty of Chemical Technology, University of Chemistry and Technology Prague, Technická 5, 166 28, Czech Republic

   Leiden University

3. Cas van der Horst Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden University

   Oncode Institute

4. Jesse Maasland Aachen

   Leiden University

   Affiliation as printed

   Leiden University

5. Edith van der Nol Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden University

   Oncode Institute

6. Andrius Bernatavicius Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden University

   Oncode Institute

7. Gerard J. P. van Westen Aachen

   Leiden University

   Affiliation as printed

   Leiden University

8. Laura H. Heitman Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden University

   Oncode Institute

9. Sebastian J. Pomplun Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   Leiden University

   Oncode Institute