| Autor: |
Vaz RJ; Hoechst Marion Roussel Inc., Cincinnati, OH 45215, USA., McLean LR, Pelton JT |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of computer-aided molecular design [J Comput Aided Mol Des] 1998 Mar; Vol. 12 (2), pp. 99-110. |
| DOI: |
10.1023/a:1007969517376 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
Full text from SpringerLink