9GHY

Cyclophilin A in complex with Sanglifehrin A analogue (2R,3S,7S,10S,E)-10-(3-aminopropyl)-2,7-dimethylspiro[3,8,11-triaza-1(2,7)-quinolina-5(3,1)-pyridazinacyclopentadecaphanene-13,5'-[1,3]dioxan]-14-ene-4,6,9,12-tetraone

This is a non-PDB format compatible entry.

Summary for 9GHY

• Entry DOI: 10.2210/pdb9ghy/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase A, (2R,3S,7S,10S,E)-10-(3-aminopropyl)-2,7-dimethylspiro[3,8,11-triaza-1(2,7)-quinolina-5(3,1)-pyridazinacyclopentadecaphanene-13,5'-[1,3]dioxan]-14-ene-4,6,9,12-tetraone, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: cyclophilin a, sanglifehrin a, inhibitor, complex, isomerase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 18874.86

Authors

Meyners, C.,Dreizler, J.K.,Hausch, F. (deposition date: 2024-08-16, release date: 2024-11-06, Last modification date: 2024-12-04)

Primary citation

Dreizler, J.K.,Meyners, C.,Hausch, F.
Toward Dual Targeting of Catalytic and Gatekeeper Pockets in Cyclophilins Using a Macrocyclic Scaffold.
Acs Med.Chem.Lett., 15:2012-2018, 2024

PubMed Abstract: Cyclophilins, especially cyclophilin A, are involved in a variety of diseases, including the life cycle of many viruses. An advanced macrocyclic inhibitor of cyclophilin was reported to bind the catalytic pocket but not the neighboring gatekeeper pocket. Here we describe macrocyclic cyclophilin inhibitors bearing side chains designed to reach out to the gatekeeper pocket. After establishing a suitable synthesis allowing for late-stage modification of the relevant positions, we explored this exit vector. This culminated in a rigid ornithine-resembling analogue as a versatile building block, which was also incorporated into the macrocyclic scaffold. The use of amines as the gatekeeper-engaging modality was invalidated, but the exit vector was successfully established as a promising position for future modifications. Further work is needed to identify suitable motifs to simultaneously engage the catalytic and gatekeeper pockets in this highly developed macrocyclic scaffold.

PubMed: 39563809
DOI: 10.1021/acsmedchemlett.4c00427

Experimental method

X-RAY DIFFRACTION (1.15 Å)