Collagen-binding Molecular Chaperone HSP47: Role in Intestinal Fibrosis – colonic epithelial cells and subepithelial myofibroblasts
Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
De novo design based pharmacophore query generation and virtual screening for the discovery of Hsp-47 inhibitors.
Katarkar A1, Haldar PK2, Chaudhuri K3.
Abstract
Heat shock protein-47 (Hsp-47) is exclusive collagen specific molecular chaperone involved in the maturation, processing and secretion of procollagen. Hsp-47 is consistently upregulated in several fibrotic diseases. Till date there is no potential antifibrotic small molecule drug available and Hsp-47 is known to be potential therapeutic target for fibrotic disorder and drug designing. We used the de novo drug design approach followed by pharmacophore generation and virtual screening to propose Hsp-47 based antifibrotic molecules. We used e-LEAD server for de novo drug design and ZINCPharmer for 3D pharmacophore generation and virtual screening. The virtually screened molecule may inhibit direct recruitment of collagen triple helix to interact with Hsp-47 and act as antifibrotic drug.
Copyright © 2014 Elsevier Inc. All rights reserved.
KEYWORDS:
De novo drug designing; Heat shock protein 47; Pharmacophore; Virtual screening
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Spontaneous colitis in knockout (KO) and transgenic rodents provides experimental models to study the development of mucosal inflammation and inflammatory bowel disease (Crohn’s disease and ulcerative colitis). Genetic and environmental factors, particularly the normal enteric flora, are important factors in the development of mucosal inflammation. The normal mucosal homeostasis is disrupted when there is either cytokine imbalance, abrogation of oral tolerance, alteration of epithelial barrier and function or loss of immunoregulatory cells. Some but not all immunodeficiencies, in the appropriate setting, lead to colitis. CD4+ T cells have been identified as the pathogenic T cells in colitis, which mediate inflammation by either the Th1 or the Th2 pathway. The Th1 pathway dominates most colitis models and in Crohn’s disease. In contrast, the colitis in TCR alpha KO mice shares many features of ulcerative colitis including the dominance of Th2 pathway in colonic inflammation. A major benefit of these models is in the development of therapeutic strategies for the treatment of inflammatory bowel disease.
I think I am beginning to see a problem with the mouse model that confounds understanding of human colitis.
1) The epithelial barrier is disrupted in both.
2) The mouse abdomen is small, so there may be microbial invasion of the small intestine without the barrier of human small bowel & large intestine.
On Mon, Jan 25, 2016 at 4:51 PM, Leaders in Pharmaceutical Business Intelligence wrote:
> 2012pharmaceutical posted: “Collagen-binding Molecular Chaperone HSP47: > Role in Intestinal Fibrosis – colonic epithelial cells and subepithelial > myofibroblasts Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, > PhD, RN Circulation. 2000 ” >