2XNI

Protein-ligand complex of a novel macrocyclic HCV NS3 protease inhibitor derived from amino cyclic boronates

Summary for 2XNI

• Entry DOI: 10.2210/pdb2xni/pdb
• Related: 2XCF 2XCN
• Descriptor: NS3 PROTEASE, NS4A COFACTOR, (1-{[(10-tert-butyl-15,15-dimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19,23,23a-tetradecahydro-1H,5H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosin-7(3H)-yl)carbonyl]amino}-3-hydroxypropyl)(trihydroxy)borate(1-), ... (6 entities in total)
• Functional Keywords: hydrolase-hydrolase regulator complex, serine protease, hydrolase/hydrolase regulator
• Biological source: HEPATITIS C VIRUS; More
• Total number of polymer chains: 4
• Total formula weight: 47660.99

Authors

Li, X.,Zhang, Y.-K.,Liu, Y.,Ding, C.Z.,Zhou, Y.,Li, Q.,Plattner, J.J.,Baker, S.J.,Zhang, S.,Kazmierski, W.M.,Wright, L.L.,Smith, G.K.,Grimes, R.M.,Crosby, R.M.,Creech, K.L.,Carballo, L.H.,Slater, M.J.,Jarvest, R.L.,Thommes, P.,Hubbard, J.A.,Convery, M.A.,Nassau, P.M.,McDowell, W.,Skarzynski, T.J.,Qian, X.,Fan, D.,Liao, L.,Ni, Z.-J.,Pennicott, L.E.,Zou, W.,Wright, J. (deposition date: 2010-08-02, release date: 2011-08-17, Last modification date: 2024-11-13)

Primary citation

Li, X.,Zhang, Y.,Liu, Y.,Ding, C.Z.,Zhou, Y.,Li, Q.,Plattner, J.J.,Baker, S.J.,Zhang, S.,Kazmierski, W.M.,Wright, L.L.,Smith, G.K.,Grimes, R.M.,Crosby, R.M.,Creech, K.L.,Carballo, L.H.,Slater, M.J.,Jarvest, R.L.,Thommes, P.,Hubbard, J.A.,Convery, M.A.,Nassau, P.M.,Mcdowell, W.,Skarzynski, T.J.,Qian, X.,Fan, D.,Liao, L.,Ni, Z.-J.,Pennicott, L.E.,Zou, W.,Wright, J.
Novel Macrocyclic Hcv Ns3 Protease Inhibitors Derived from Alpha-Amino Cyclic Boronates.
Bioorg.Med.Chem.Lett., 20:5695-, 2010

PubMed Abstract: A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.

PubMed: 20801653
DOI: 10.1016/J.BMCL.2010.08.022

Experimental method

X-RAY DIFFRACTION (3.3 Å)