2BMG

Crystal structure of factor Xa in complex with 50

Summary for 2BMG

• Entry DOI: 10.2210/pdb2bmg/pdb
• Related: 1C5M 1EZQ 1F0R 1F0S 1FAX 1FJS 1FXY 1G2L 1G2M 1HCG 1IOE 1IQE 1IQF 1IQG 1IQH 1IQI 1IQJ 1IQK 1IQL 1IQM 1IQN 1KSN 1KYE 1LPG 1LPK 1LPZ 1LQD 1MQ5 1MQ6 1MSX 1NFU 1NFW 1NFX 1NFY 1NL8 1P0S 1V3X 1WU1 1XKA 1XKB 2BOH 2BOK 2BQ6 2BQ7 2BQW
• Descriptor: COAGULATION FACTOR X, CALCIUM ION, 3-[2-(2,4-DICHLOROPHENYL)ETHOXY]-4-METHOXY-N-[(1-PYRIDIN-4-YLPIPERIDIN-4-YL)METHYL]BENZAMIDE, ... (5 entities in total)
• Functional Keywords: thrombosis, protein inhibitor complex, blood coagulation factor, serine proteinase, drug design, hydrolase
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 32748.05

Authors

Schreuder, H.,Matter, H.,Will, D.W.,Nazare, M.,Laux, V.,Wehner, V.,Loenze, P.,Liesum, A. (deposition date: 2005-03-14, release date: 2006-03-08, Last modification date: 2024-11-20)

Primary citation

Matter, H.,Will, D.W.,Nazare, M.,Schreuder, H.,Laux, V.,Wehner, V.,Liesum, A.
Structural Requirements for Factor Xa Inhibition by 3-Oxybenzamides with Neutral P1 Substituents: Combining X-Ray Crystallography, 3D-Qsar and Tailored Scoring Functions
J.Med.Chem., 48:3290-, 2005

PubMed Abstract: The design, synthesis, and structure-activity relationship of 3-oxybenzamides as potent inhibitors of the coagulation protease factor Xa are described on the basis of X-ray structures, privileged structure motifs, and SAR information. A total of six X-ray structures of fXa/inhibitor complexes led us to identify the major protein-ligand interactions. The binding mode is characterized by a lipophilic dichlorophenyl substituent interacting with Tyr228 in the protease S1 pocket, while polar parts are accommodated in S4. This alignment in combination with docking allowed derivation of 3D-QSAR models and tailored scoring functions to rationalize biological affinity and provide guidelines for optimization. The resulting models showed good correlation coefficients and predictions of external test sets. Furthermore, they correspond to binding site topologies in terms of steric, electrostatic, and hydrophobic complementarity. Two approaches to derive tailored scoring functions combining binding site and ligand information led to predictive models with acceptable predictions of the external set. Good correlations to experimental affinities were obtained for both AFMoC (adaptation of fields for molecular comparison) and the novel TScore function. The SAR information from 3D-QSAR and tailored scoring functions agrees with all experimental data and provides guidelines and reasonable activity estimations for novel fXa inhibitors.

PubMed: 15857135
DOI: 10.1021/JM049187L

Experimental method

X-RAY DIFFRACTION (2.7 Å)