6Z48

Crystal structure of Thrombin in complex with macrocycle X1vE

Summary for 6Z48

• Entry DOI: 10.2210/pdb6z48/pdb
• Descriptor: Thrombin light chain, Thrombin heavy chain, SODIUM ION, ... (5 entities in total)
• Functional Keywords: serine protease, blood clotting factor, inhibition, macrocycle, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 138103.82

Authors

Angelini, A.,Habeshian, S.,Heinis, C.,Cendron, L. (deposition date: 2020-05-23, release date: 2022-06-01, Last modification date: 2024-11-13)

Primary citation

Habeshian, S.,Merz, M.L.,Sangouard, G.,Mothukuri, G.K.,Schuttel, M.,Bognar, Z.,Diaz-Perlas, C.,Vesin, J.,Bortoli Chapalay, J.,Turcatti, G.,Cendron, L.,Angelini, A.,Heinis, C.
Synthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale.
Nat Commun, 13:3823-3823, 2022

PubMed Abstract: Macrocycles have excellent potential as therapeutics due to their ability to bind challenging targets. However, generating macrocycles against new targets is hindered by a lack of large macrocycle libraries for high-throughput screening. To overcome this, we herein established a combinatorial approach by tethering a myriad of chemical fragments to peripheral groups of structurally diverse macrocyclic scaffolds in a combinatorial fashion, all at a picomole scale in nanoliter volumes using acoustic droplet ejection technology. In a proof-of-concept, we generate a target-tailored library of 19,968 macrocycles by conjugating 104 carboxylic-acid fragments to 192 macrocyclic scaffolds. The high reaction efficiency and small number of side products of the acylation reactions allowed direct assay without purification and thus a large throughput. In screens, we identify nanomolar inhibitors against thrombin (K = 44 ± 1 nM) and the MDM2:p53 protein-protein interaction (K MDM2 = 43 ± 18 nM). The increased efficiency of macrocycle synthesis and screening and general applicability of this approach unlocks possibilities for generating leads against any protein target.

PubMed: 35780129
DOI: 10.1038/s41467-022-31428-8

Experimental method

X-RAY DIFFRACTION (2.27 Å)