Combining AlphaFold with Focused Virtual Library Design in the Development of Novel CCR2 and CCR5 Antagonists

Journal of Chemical Information and Modeling, vol. 65, pp. 12398–12409

Abstract

High Resolution Image Download MS PowerPoint Slide CC chemokine receptor (CCR) 2 and 5 are G protein-coupled receptors that play a crucial role in immunohomeostasis. Accordingly, overactivation of their signaling pathways is involved in various immunopathologies and cancer. Extensive research focusing on discovering CCR2 and CCR5 orthosteric antagonists, ultimately resulted in some clinical success, but the area of intracellular allosteric modulators is still underexplored and the move from orthosteric to allosteric modulation could be an interesting paradigm shift. To this end, we document the development of novel CCR2 and CCR5 intracellular allosteric antagonists through a virtual screen on a small combinatorial library derived from existing CCR2, CCR5, and CCR4 ligands. Using a molecular docking approach, the created library was screened in its entirety utilizing a refined AlphaFold model of CCR5 based on the crystal structure of its close homologue, CCR2. The screening resulted in the identification of several virtual hits, out of which one was developed further by in-house synthesis. In total, 18 analogues were prepared and experimentally evaluated for their binding affinity for CCR2 and functional inhibition on CCR5. This expeditious and simple workflow beginning from docking to compound evaluation identified 3 hits for CCR2 ( K i = 1.3–6 μM) and 1 hit (IC 50 = 10.8 μM) for CCR5. The obtained structure–activity relationships were also further rationalized using structural information available for both CCR5 and CCR2 providing valuable insights for future development of intracellular allosteric ligands.

Authors 10

1. Khaled Essa Aachen Division of Medicinal Chemistry Leiden Academic Centre for Drug Research

   Leiden University · Oncode Institute

   Affiliation as printed

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR)

   Leiden University

   Oncode Institute

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands

   Oncode Institute, 2333 CC Leiden, The Netherlands

2. Kian Noorman van der Dussen Aachen Division of Medicinal Chemistry Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR)

   Leiden University

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands

3. Yao Yao Aachen Division of Medicinal Chemistry Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR)

   Leiden University

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands

4. Bente T.M. Bleijs Aachen Division of Medicinal Chemistry Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR)

   Leiden University

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands

5. Natalia V. Ortiz Zacarı́as Aachen Division of Medicinal Chemistry Leiden Academic Centre for Drug Research

   Leiden University · Oncode Institute

   Affiliation as printed

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR)

   Leiden University

   Oncode Institute

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands

   Oncode Institute, 2333 CC Leiden, The Netherlands

6. Laura H. Heitman Aachen Division of Medicinal Chemistry Leiden Academic Centre for Drug Research

   Leiden University · Oncode Institute

   Affiliation as printed

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR)

   Leiden University

   Oncode Institute

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands

   Oncode Institute, 2333 CC Leiden, The Netherlands

7. Gerard J. P. van Westen Aachen Division of Medicinal Chemistry Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR)

   Leiden University

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands

8. Willem Jespers

   University of Groningen

   Affiliation as printed

   Department of Medicinal Chemistry, Photopharmacology and Imaging, Groningen, Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands

9. Daan van der Es corresponding Aachen Division of Medicinal Chemistry Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR)

   Leiden University

   Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands

10. Martin Šícho corresponding Aachen Division of Medicinal Chemistry Leiden Academic Centre for Drug Research

    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

    Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR)

    Leiden University

    Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2333 CC Leiden, The Netherlands