8R41

Structure of CHI3L1 in complex with inhibitor 1

Summary for 8R41

• Entry DOI: 10.2210/pdb8r41/pdb
• Descriptor: Chitinase-3-like protein 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ~{N}-[2-(4-bromophenyl)ethyl]-~{N}-(2-methoxyethyl)-1-(1,3-thiazol-2-yl)piperidin-4-amine, ... (6 entities in total)
• Functional Keywords: chitinase-3-like-1, inhibitors, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 87764.73

Authors

Nowak, E.,Napiorkowska-Gromadzka, A.,Nowotny, M. (deposition date: 2023-11-10, release date: 2024-03-13, Last modification date: 2024-10-16)

Primary citation

Czestkowski, W.,Krzeminski, L.,Piotrowicz, M.C.,Mazur, M.,Pluta, E.,Andryianau, G.,Koralewski, R.,Matyszewski, K.,Olejniczak, S.,Kowalski, M.,Lisiecka, K.,Koziel, R.,Piwowar, K.,Papiernik, D.,Nowotny, M.,Napiorkowska-Gromadzka, A.,Nowak, E.,Niedzialek, D.,Wieczorek, G.,Siwinska, A.,Rejczak, T.,Jedrzejczak, K.,Mulewski, K.,Olczak, J.,Zaslona, Z.,Golebiowski, A.,Drzewicka, K.,Bartoszewicz, A.
Structure-Based Discovery of High-Affinity Small Molecule Ligands and Development of Tool Probes to Study the Role of Chitinase-3-Like Protein 1.
J.Med.Chem., 67:3959-3985, 2024

PubMed Abstract: Chitinase-3-like-1 (CHI3L1), also known as YKL-40, is a glycoprotein linked to inflammation, fibrosis, and cancer. This study explored CHI3L1's interactions with various oligosaccharides using microscale thermophoresis (MST) and AlphaScreen (AS). These investigations guided the development of high-throughput screening assays to assess interference of small molecules in binding between CHI3L1 and biotinylated small molecules or heparan sulfate-based probes. Small molecule binders of YKL-40 were identified in our chitotriosidase inhibitors library with MST and confirmed through X-ray crystallography. Based on cocrystal structures of potent hit compounds with CHI3L1, small molecule probes and were designed for an AS assay. Structure-based optimization led to compounds and with nanomolar activities and drug-like properties. Additionally, an orthogonal AS assay using biotinylated heparan sulfate as a probe was developed. The compounds' affinity showed a significant correlation in both assays. These screening tools and compounds offer novel avenues for investigating the role of CHI3L1.

PubMed: 38427954
DOI: 10.1021/acs.jmedchem.3c02255

Experimental method

X-RAY DIFFRACTION (2.25 Å)