4TOT

Crystal structure of rat cyclophilin D in complex with a potent nonimmunosuppressive inhibitor

Summary for 4TOT

• Entry DOI: 10.2210/pdb4tot/pdb
• Related PRD ID: PRD_002115
• Descriptor: Peptidyl-prolyl cis-trans isomerase F, mitochondrial, nonimmunosuppressive inhibitor, HEXAETHYLENE GLYCOL, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, cyclosporin, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Mitochondrion matrix : P29117
• Total number of polymer chains: 8
• Total formula weight: 77541.41

Authors

Knapp, M.S.,Elling, R.A. (deposition date: 2014-06-06, release date: 2014-11-12, Last modification date: 2024-04-03)

Primary citation

Fu, J.,Tjandra, M.,Becker, C.,Bednarczyk, D.,Capparelli, M.,Elling, R.,Hanna, I.,Fujimoto, R.,Furegati, M.,Karur, S.,Kasprzyk, T.,Knapp, M.,Leung, K.,Li, X.,Lu, P.,Mergo, W.,Miault, C.,Ng, S.,Parker, D.,Peng, Y.,Roggo, S.,Rivkin, A.,Simmons, R.L.,Wang, M.,Wiedmann, B.,Weiss, A.H.,Xiao, L.,Xie, L.,Xu, W.,Yifru, A.,Yang, S.,Zhou, B.,Sweeney, Z.K.
Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition.
J.Med.Chem., 57:8503-8516, 2014

PubMed Abstract: Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

PubMed: 25310383
DOI: 10.1021/jm500862r

Experimental method

X-RAY DIFFRACTION (2.39 Å)