PDBsum entry 1lqe

Hydrolase

PDB id: 1lqe

Contents

Protein chain

223 a.a. *

Ligands

SO4

IMA

Metals

_CA

Waters ×139

* Residue conservation analysis

PDB id:

1lqe

Name:

Hydrolase

Title:

Crystal structure of trypsin in complex with 79.

Structure:

Trypsin. Chain: a. Synonym: beta-trypsin. Ec: 3.4.21.4

Source:

Bos taurus. Cattle. Organism_taxid: 9913. Organ: pancreas

Resolution:

2.20Å R-factor: 0.166

Authors:

H.A.Schreuder,A.Liesum

Key ref:

H.Matter et al. (2002). Design and quantitative structure-activity relationship of 3-amidinobenzyl-1H-indole-2-carboxamides as potent, nonchiral, and selective inhibitors of blood coagulation factor Xa. J Med Chem, 45, 2749-2769. PubMed id: 12061878 DOI: 10.1021/jm0111346

Date:

10-May-02 Release date: 10-May-03

Protein chain

P00760  (TRY1_BOVIN) -  Serine protease 1 from Bos taurus

Seq: 246 a.a.

Struc: 223 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.21.4 - trypsin.
• Reaction: Preferential cleavage: Arg-|-Xaa, Lys-|-Xaa.

DOI no: 10.1021/jm0111346

J Med Chem 45:2749-2769 (2002)

PubMed id: 12061878

Design and quantitative structure-activity relationship of 3-amidinobenzyl-1H-indole-2-carboxamides as potent, nonchiral, and selective inhibitors of blood coagulation factor Xa.

H.Matter, E.Defossa, U.Heinelt, P.M.Blohm, D.Schneider, A.Müller, S.Herok, H.Schreuder, A.Liesum, V.Brachvogel, P.Lönze, A.Walser, F.Al-Obeidi, P.Wildgoose.

ABSTRACT

A series of 138 nonchiral 3-amidinobenzyl-1H-indole-2-carboxamides and analogues as inhibitors of the blood coagulation enzyme factor Xa (fXa) were designed, synthesized, and investigated by X-ray structure analysis and 3D quantitative structure-activity relationship (QSAR) studies (CoMFA, CoMSIA) in order to identify important protein-ligand interactions responsible for biological affinity and selectivity. Several compounds from this series are highly potent and selective inhibitors of this important enzyme linking extrinsic and intrinsic coagulation pathways. To rationalize biological affinity and to provide guidelines for further design, all compounds were docked into the factor Xa binding site. Those docking studies were based on X-ray structures of factor Xa in complex with literature-known inhibitors. It was possible to validate those binding modes by four X-ray crystal structures of representative ligands in factor Xa, while one ligand was additionally crystallized in trypsin to rationalize requirements for selective factor Xa inhibition. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r(2) values using the leave-one-out method and repeated analyses using two randomly chosen cross-validation groups plus randomization of biological activities. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which were found to correspond to experimentally determined factor Xa binding site topology in terms of steric, electrostatic, and hydrophobic complementarity. Subsets selected as smaller training sets using 2D fingerprints and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable correlation coefficients and a high predictive power. The final quantitative SAR information agrees with all experimental data for the binding topology and thus provides reasonable activity predictions for novel factor Xa inhibitors.