4U01

HCV NS3/4A serine protease in complex with 6570

Summary for 4U01

• Entry DOI: 10.2210/pdb4u01/pdb
• Descriptor: Non-structural 3 protease, NS4A protein, (2S,3aS,10Z,11aS,12aR)-2-({8-fluoro-7-methoxy-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-N-[(1-methylcyclopropyl)sulfonyl]-4,14-dioxo-1,2,3,3a,4,5,6,7,8,9,11a,12,13,14-tetradecahydro-12aH-cyclopropa[m]pyrrolo[1,2-c][1,3,6]triazacyclotetradecine-12a-carboxamide, ... (5 entities in total)
• Functional Keywords: hvc, ns3/4a protease, drug design, proteros biostructures gmbh, hydrolase
• Biological source: Hepatitis C virus (isolate Con1); More
• Total number of polymer chains: 18
• Total formula weight: 215982.08

Authors

Parsy, C.C.,Alexandre, F.-R.,Brandt, G.,Caillet, C.,Chaves, D.,Derock, M.,Gloux, D.,Griffon, Y.,Lallos, L.B.,Leroy, F.,Liuzzi, M.,Loi, A.-G.,Mayes, B.,Moulat, L.,Moussa, A.,Chiara, M.,Roques, V.,Rosinovsky, E.,Seifer, M.,Stewart, A.,Wang, J.,Standring, D.,Surleraux, D. (deposition date: 2014-07-11, release date: 2015-07-29, Last modification date: 2024-05-08)

Primary citation

Parsy, C.C.,Alexandre, F.R.,Bidau, V.,Bonnaterre, F.,Brandt, G.,Caillet, C.,Cappelle, S.,Chaves, D.,Convard, T.,Derock, M.,Gloux, D.,Griffon, Y.,Lallos, L.B.,Leroy, F.,Liuzzi, M.,Loi, A.G.,Moulat, L.,Chiara, M.,Rahali, H.,Roques, V.,Rosinovsky, E.,Savin, S.,Seifer, M.,Standring, D.,Surleraux, D.
Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320.
Bioorg.Med.Chem.Lett., 25:5427-5436, 2015

PubMed Abstract: Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.

PubMed: 26410074
DOI: 10.1016/j.bmcl.2015.09.009

Experimental method

X-RAY DIFFRACTION (2.8 Å)