(R)-3-amidinophenylalanine-derived inhibitors of factor Xa with a novel active-site binding mode

被引:14
作者
Mueller, MM
Sperl, S
Stürzebecher, J
Bode, W
Moroder, L [1 ]
机构
[1] Max Planck Inst Biochem, D-82152 Martinsried, Germany
[2] Wilex AG, D-81675 Munich, Germany
[3] Univ Jena, Zentrum Vask Biol & Med Biochem, D-99089 Erfurt, Germany
关键词
(R)-3-amidinophenylalanine; factor Xa; novel active-site binding mode; S1; subregion; synthetic inhibitors; X-ray crystal structure;
D O I
10.1515/BC.2002.130
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A putative nonsubstrate like binding mode of (R)-3- amidinophenylalanine derivatives to factor Xa, as derived from modeling experiments based on Xray analysis of their complexes with trypsin, was used to design a new generation of inhibitors. However, the resulting inhibitory potencies were not at all consistent with the working assumption, although with an adamantylureido derivative of (R)-3-amidinophenylalanine phenetyl amide a highly selective nanomolar inhibition of factor Xa was achieved. The Xray analysis of the complex of this ligand with factor Xa revealed an unexpected new binding mode, of which the most important feature is the interaction of the Cterminal aryl moiety with a hydrophobic subregion of the S1 subsite, while the adamantyl group occupies the hydrophobic S3/S4 subsites of the enzyme.
引用
收藏
页码:1185 / 1191
页数:7
相关论文
共 28 条
[1]   Factor Xa inhibitors by classical and combinatorial chemistry [J].
Al-Obeidi, F ;
Ostrem, JA .
DRUG DISCOVERY TODAY, 1998, 3 (05) :223-231
[2]   Factor Xa inhibitors [J].
Al-Obeidi, F ;
Ostrem, JA .
EXPERT OPINION ON THERAPEUTIC PATENTS, 1999, 9 (07) :931-953
[3]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[4]  
BANNER DW, 1991, J BIOL CHEM, V266, P20085
[5]   GEOMETRY OF BINDING OF THE BENZAMIDINE-BASED AND ARGININE-BASED INHIBITORS N-ALPHA-(2-NAPHTHYL-SULFONYL-GLYCYL)-DL-PARA-AMIDINOPHENYLALANYL-PIPERIDINE (NAPAP) AND (2R,4R)-4-METHYL-1-[N-ALPHA-(3-METHYL-1,2,3,4-TETRAHYDRO-8-QUINOLINESULPHONYL)-L-ARGINYL]-2-PIPERIDINE CARBOXYLIC-ACID (MQPA) TO HUMAN ALPHA-THROMBIN - X-RAY CRYSTALLOGRAPHIC DETERMINATION OF THE NAPAP-TRYPSIN COMPLEX AND MODELING OF NAPAP-THROMBIN AND MQPA-THROMBIN [J].
BODE, W ;
TURK, D ;
STURZEBECHER, J .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1990, 193 (01) :175-182
[6]   X-ray structure of active site-inhibited clotting factor Xa - Implications for drug design and substrate recognition [J].
Brandstetter, H ;
Kuhne, A ;
Bode, W ;
Huber, R ;
vonderSaal, W ;
Wirthensohn, K ;
Engh, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (47) :29988-29992
[7]   REFINED 2.3-ANGSTROM X-RAY CRYSTAL-STRUCTURE OF BOVINE THROMBIN COMPLEXES FORMED WITH THE BENZAMIDINE AND ARGININE-BASED THROMBIN INHIBITORS NAPAP, 4-TAPAP AND MQPA - A STARTING POINT FOR IMPROVING ANTITHROMBOTICS [J].
BRANDSTETTER, H ;
TURK, D ;
HOEFFKEN, HW ;
GROSSE, D ;
STURZEBECHER, J ;
MARTIN, PD ;
EDWARDS, BFP ;
BODE, W .
JOURNAL OF MOLECULAR BIOLOGY, 1992, 226 (04) :1085-1099
[8]   Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].
Brunger, AT ;
Adams, PD ;
Clore, GM ;
DeLano, WL ;
Gros, P ;
Grosse-Kunstleve, RW ;
Jiang, JS ;
Kuszewski, J ;
Nilges, M ;
Pannu, NS ;
Read, RJ ;
Rice, LM ;
Simonson, T ;
Warren, GL .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921
[9]   THE DETERMINATION OF ENZYME INHIBITOR CONSTANTS [J].
DIXON, M .
BIOCHEMICAL JOURNAL, 1953, 55 (01) :170-171
[10]   OPTIMIZATION OF CONDITIONS FOR THE CATALYTIC EFFECT OF THE FACTOR-IXA - FACTOR-VIII COMPLEX - PROBABLE ROLE OF THE COMPLEX IN THE AMPLIFICATION OF BLOOD-COAGULATION [J].
ELODI, S ;
VARADI, K .
THROMBOSIS RESEARCH, 1979, 15 (5-6) :617-629