Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists.

Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions.

Pharmacological modulation of chemokine receptor function.

G protein-coupled chemokine receptors and their peptidergic ligands are interesting therapeutic targets due to their involvement in various immune-related diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, HIV-1 infection and cancer. To tackle these diseases, a lot of effort has been focused on discovery and development of small-molecule chemokine receptor antagonists. This has been rewarded by the market approval of two novel chemokine receptor inhibitors, AMD3100 (CXCR4) and Maraviroc (CCR5) for stem cell mobilization and treatment of HIV-1 infection respectively. The recent GPCR crystal structures together with mutagenesis and pharmacological studies have aided in understanding how small-molecule ligands interact with chemokine receptors. Many of these ligands display behaviour deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. This review aims to give an overview of the evidence supporting modulation of this intriguing receptor family by a range of ligands, including small molecules, peptides and antibodies. Moreover, the computer-assisted modelling of chemokine receptor-ligand interactions is discussed in view of GPCR crystal structures. Finally, the implications of concepts such as functional selectivity and chemokine receptor dimerization are considered.

C(X)CR in silico: Computer-aided prediction of chemokine receptor-ligand interactions.

This review will focus on the construction, refinement, and validation of chemokine receptor models for the purpose of structure-based virtual screening and ligand design. The review will present a comparative analysis of ligand binding pockets in chemokine receptors, including a review of the recently released CXCR4 X-ray structures, and their implication on chemokine receptor (homology) modeling. The recommended protein-ligand modeling procedure as well as the use of experimental anchors to steer the modeling procedure is discussed and an overview of several successful structure-based ligand discovery and design studies is provided. This review shows that receptor models, despite structural inaccuracies, can be efficiently used to find novel ligands for chemokine receptors.:

Use of the low-molecular-weight heparin reviparin to prevent deep-vein thrombosis after leg injury requiring immobilization.

BACKGROUND: Deep-vein thrombosis is a well-recognized complication after trauma to the legs and subsequent immobilization, but there are no generally accepted approaches to preventing this complication. METHODS: We performed a prospective, double-blind, placebo-controlled trial to evaluate the efficacy and safety of subcutaneous reviparin (1750 anti-Xa units given once daily) in 440 patients who required immobilization in a plaster cast or brace for at least five weeks after a leg fracture or rupture of the Achilles tendon. The study drug was given throughout the period of immobilization. Venography of the injured leg was performed within one week after removal of the plaster cast or brace, or earlier if there were symptoms suggesting deep-vein thrombosis. RESULTS: Data on efficacy and end points were available for 371 patients. Deep-vein thrombosis was diagnosed in 17 of the 183 patients randomly assigned to receive reviparin (9 percent) and in 35 of the 188 patients randomly assigned to receive placebo (19 percent) (odds ratio, 0.45; 95 percent confidence interval, 0.24 to 0.82). Most of the thromboses were distal (14 in the reviparin group and 25 in the placebo group). There were two cases of pulmonary embolism, both in patients in the placebo group who also had proximal deep-vein thrombosis. There were no differences between the two groups with respect to bleeding or other adverse events. CONCLUSIONS: Deep-vein thrombosis is common in persons with leg injury requiring prolonged immobilization. Reviparin given once daily appears to be effective and safe in reducing the risk of this complication.