Enabling design of selective antagonists for the CC Chemokine receptor 2A (CCR2A)

In a partnership with Boehringer Ingelheim (BI), leadXpro generated protein and provided the X-ray structure data to advance their drug discovery programs on CCR2, a key target in several autoimmune and neurological disorders.

After extensive construct screening and optimization, the team at leadXpro were able to produce a 2.7 Å crystal structure of CCR2 with bound antagonist – this breakthrough came through the use of in meso in situ serial X-ray crystallography (IMISX), a method that is especially useful when working with fragile membrane protein crystals (1,3). The structural data aided Boehringer’s chemistry efforts to optimize drug residence time (2).

Fig. 3 from (3): A) Orthosteric site superposition of 5T1A (white) and 6GPX (blue) shows that the binding sites are structurally and conformationally highly conserved. The chemically distinct ligands BMS-681 (green) and MK-0812 (yellow) occupy overlapping sites in the receptor and form unique contacts within the binding pocket. The main difference consists in the electrostatic interaction of the E2917.39 side chain with MK- 0812. (B) Predicted binding pose of compound 15a (yellow) superimposed with MK-0812 (white). Indane contacting residues are shown as van der Waals spheres (blue); three water molecules that are potentially displaced are shown as red spheres.
Fig. 3 from (3): A) Orthosteric site superposition of 5T1A (white) and 6GPX (blue) shows that the binding sites are structurally and conformationally highly conserved. The chemically distinct ligands BMS-681 (green) and MK-0812 (yellow) occupy overlapping sites in the receptor and form unique contacts within the binding pocket. The main difference consists in the electrostatic interaction of the E2917.39 side chain with MK- 0812. (B) Predicted binding pose of compound 15a (yellow) superimposed with MK-0812 (white). Indane contacting residues are shown as van der Waals spheres (blue); three water molecules that are potentially displaced are shown as red spheres.

References

1 Apel, A.-K. et al. Crystal Structure of CC Chemokine Receptor 2A in Complex with an Orthosteric Antagonist Provides Insights for the Design of Selective Antagonists. Structure, doi:10.1016/j.str.2018.10.027 (2018).

2 Magarkar, A., Schnapp, G., Apel, A.-K., Seeliger, D. & Tautermann, C. S. Enhancing Drug Residence Time by Shielding of Intra-Protein Hydrogen Bonds: A Case Study on CCR2 Antagonists. ACS Medicinal Chemistry Letters 10, 324-328, doi:10.1021/acsmedchemlett.8b00590 (2019).

3 Cheng, R., Huang, C.-Y., Hennig, M., Nar, H. & Schnapp, G. In situ crystallography as an emerging method for structure solution of membrane proteins: the case of CCR2A. FEBS J. 287, 866-873, doi:10.1111/febs.15098 (2020).

Icon from (3)