Evaluation of proposed modes of binding of (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-am idino- 2- naphthyl)propanoic acid hydrochloride and some analogs to factor Xa using a comparative molecular field analysis.
The binding mode of (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-ami dino-2- naphthyl)propanoic acid hydrochloride (DX-9065a, 4) to Factor Xa is examined using inhibition data for a series of analogs that have a hydrophobic group as well as basic or dibasic functionality. Comparative molecular field analysis is utilized on a series of DX-9065a analogs in a series of proposed alternative binding modes. A quantitative measure is provided that distinguishes between the proposed binding modes that describes 'how well' the binding mode explains the structure-activity relationship or the best 3D QSAR agrees with the crystallographically determined binding mode. The best model is in agreement with recently available data [Brandstetter et al., J. Biol. Chem., 271 (1996) 29988]. The highest statistical correlation occurs with the second basic group accommodated in the vicinity of Glu97 and a hydrophobic group accommodated in the pocket defined by Phe174, Tyr99 and Trp215. Also, the best model arises when the conformation of the Glu97 side chain is modified such that an H-bond interaction is maintained with the inhibitor if possible. The model also shows a tightening of the S1 pocket as is shown in the recent data described above.
Vaz
R J
RJ
Hoechst Marion Roussel Inc., Cincinnati, OH 45215, USA.
McLean
L R
LR
Pelton
J T
JT
D003461:Crystallography; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism*; D065427:Factor Xa Inhibitors; D008956:Models, Chemical; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism*; D011422:Propionates / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D016415:Sequence Alignment
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D010975:Platelet Aggregation Inhibitors; D011422:Propionates; D015951:Factor Xa