High-resolution crystal structures of factor XIa coagulation factor in complex with nonbasic high-affinity synthetic inhibitors

被引：14

作者：

Fradera, Xavier ^{[1
]}

Kazemier, Bert ^{[2
]}

Carswell, Emma ^{[1
]}

Cooke, Andrew ^{[1
]}

Oubrie, Arthur ^{[2
]}

Hamilton, William ^{[1
]}

Dempster, Maureen ^{[1
]}

Krapp, Stephan ^{[3
]}

Nagel, Susanna ^{[3
]}

Jestel, Anja ^{[3
]}

机构：

[1] Merck Res Labs, MSD, Newhouse ML1 5SH, Lanark, Scotland

[2] Merck Res Labs, MSD, NL-5340 BH Oss, Netherlands

[3] Proteros Biostruct GmbH, D-82152 Planegg Martinsried, Germany

来源：

ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS | 2012年 / 68卷

关键词：

BIOLOGICAL EVALUATION; FACTOR XA; DESIGN; DISCOVERY; RESIDUES; WARFARIN;

D O I：

10.1107/S1744309112009037

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Factor XI (FXI) is a key enzyme in the coagulation pathway and an attractive target for the development of anticoagulant drugs. A small number of high-resolution crystal structures of FXIa in complex with small synthetic inhibitors have been published to date. All of these ligands have a basic P1 group and bind exclusively in the nonprime side of the active site of FXIa. Here, two structures of FXIa in complex with nonbasic inhibitors that occupy both the prime and nonprime sides of the active site are presented. These new structures could be valuable in the design and optimization of new FXIa synthethic inhibitors.

引用

页码：404 / 408

页数：5

共 27 条

[1]

[Anonymous], 2009, ANGEW CHEM

[2]

[Anonymous], [No title captured], Patent No. 2007070826

[3] More than a Simple Lipophilic Contact: A Detailed Thermodynamic Analysis of Nonbasic Residues in the S1 Pocket of Thrombin [J].

Baum, Bernhard ;

Mohamed, Menshawy ;

Zayed, Mohamed ;

Gerlach, Christof ;

Heine, Andreas ;

Hangauer, David ;

Klebe, Gerhard .

JOURNAL OF MOLECULAR BIOLOGY, 2009, 390 (01) :56-69

[4] Clavatadine A, a natural product with selective recognition and irreversible inhibition of factor XIa [J].

Buchanan, Malcolm S. ;

Carroll, Anthony R. ;

Wessling, Deborah ;

Jobling, Michael ;

Avery, Vicky M. ;

Davis, Rohan A. ;

Feng, Yunjiang ;

Xue, Yafeng ;

Oster, Linda ;

Fex, Tomas ;

Deinum, Johanna ;

Hooper, John N. A. ;

Quinn, Ronald J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (12) :3583-3587

[5] Dabigatran versus Warfarin in Patients with Atrial Fibrillation. [J].

Connolly, Stuart J. ;

Ezekowitz, Michael D. ;

Yusuf, Salim ;

Eikelboom, John ;

Oldgren, Jonas ;

Parekh, Amit ;

Pogue, Janice ;

Reilly, Paul A. ;

Themeles, Ellison ;

Varrone, Jeanne ;

Wang, Susan ;

Alings, Marco ;

Xavier, Denis ;

Zhu, Jun ;

Diaz, Rafael ;

Lewis, Basil S. ;

Darius, Harald ;

Diener, Hans-Christoph ;

Joyner, Campbell D. ;

Wallentin, Lars .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (12) :1139-1151

[6]

Corte J. R., 2009, Patent WO, Patent No. [2009/114677 A1, 2009114677]

[7] Synthesis, SAR exploration, and X-ray crystal structures of factor XIa inhibitors containing an α-ketothiazole arginine [J].

Deng, HF ;

Bannister, TD ;

Jin, L ;

Babine, RE ;

Quinn, J ;

Nagafuji, P ;

Celatka, CA ;

Lin, J ;

Lazarova, TI ;

Rynkiewicz, MJ ;

Bibbins, F ;

Pandey, P ;

Gorga, J ;

Meyers, HV ;

Abdel-Meguid, SS ;

Strickler, JE .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (11) :3049-3054

[8] Coot:: model-building tools for molecular graphics [J].

Emsley, P ;

Cowtan, K .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2126-2132

[9] Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis -: A randomized trial [J].

Fiessinger, JN ;

Huisman, MV ;

Davidson, BL ;

Bounameaux, H ;

Francis, CW ;

Eriksson, H ;

Lundström, T ;

Berkowitz, SD ;

Nyström, P ;

Thorsén, M ;

Ginsberg, JS .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2005, 293 (06) :681-689

[10] Structural and functional features of factor XI [J].

Gailani, D. ;

Smith, S. B. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2009, 7 :75-78

← 1 2 3 →