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
REFERENCES
|
1. |
|
|
Honzawa Y, Nakase H, Shiokawa M, Yoshino T, Imaeda H, Matsuura M, Kodama Y, Ikeuchi H, Andoh A, Sakai Y, Nagata K, Chiba T. |
|
|
Gut. 2014 Dec;63(12):1902-12. doi: 10.1136/gutjnl-2013-305632. Epub 2014 Feb 17. |
|
|
PMID: 24534724 [PubMed – indexed for MEDLINE] |
|
|
2. |
Role of heat shock protein 47 in intestinal fibrosis of experimental colitis. |
|
Kitamura H, Yamamoto S, Nakase H, Matsuura M, Honzawa Y, Matsumura K, Takeda Y, Uza N, Nagata K, Chiba T. |
|
|
Biochem Biophys Res Commun. 2011 Jan 14;404(2):599-604. doi: 10.1016/j.bbrc.2010.12.006. Epub 2010 Dec 6. |
|
|
PMID: 21144841 [PubMed – indexed for MEDLINE] |
|
|
3. |
|
|
Abe K, Ozono Y, Miyazaki M, Koji T, Shioshita K, Furusu A, Tsukasaki S, Matsuya F, Hosokawa N, Harada T, Taguchi T, Nagata K, Kohno S. |
|
|
Nephrol Dial Transplant. 2000 Apr;15(4):529-35. |
|
|
PMID: 10727549 [PubMed – indexed for MEDLINE] Free Article |
|
|
4. |
|
|
Nishino T, Miyazaki M, Abe K, Furusu A, Mishima Y, Harada T, Ozono Y, Koji T, Kohno S. |
|
|
Kidney Int. 2003 Sep;64(3):887-96. |
|
|
PMID: 12911538 [PubMed – indexed for MEDLINE] |
|
|
5. |
Involvement of heat shock protein 47 in Schistosoma japonicum-induced hepatic fibrosis in mice. |
|
Huang JQ, Tao R, Li L, Ma K, Xu L, Ai G, Fan XX, Jiao YT, Ning Q. |
|
|
Int J Parasitol. 2014 Jan;44(1):23-35. doi: 10.1016/j.ijpara.2013.08.009. Epub 2013 Dec 1. |
|
|
PMID: 24295791 [PubMed – indexed for MEDLINE] |
|
|
6. |
The collagen-specific molecular chaperone HSP47: is there a role in fibrosis? |
|
Taguchi T, Razzaque MS. |
|
|
Trends Mol Med. 2007 Feb;13(2):45-53. Epub 2006 Dec 13. |
|
|
PMID: 17169614 [PubMed – indexed for MEDLINE] |
|
|
7. |
|
|
Truchetet ME, Brembilla NC, Montanari E, Lonati P, Raschi E, Zeni S, Fontao L, Meroni PL, Chizzolini C. |
|
|
Arthritis Rheum. 2013 May;65(5):1347-56. doi: 10.1002/art.37860. |
|
|
PMID: 23335253 [PubMed – indexed for MEDLINE] Free Article |
|
|
8. |
|
|
Li Y, Wu W, Jiang YF, Wang KK. |
|
|
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2007 Aug;32(4):650-5. Chinese. |
|
|
PMID: 17767059 [PubMed – indexed for MEDLINE] Free Article |
|
|
2012pharmaceutical
Aashir Awan, Phd
Alan F. Kaul, PharmD., MS, MBA, FCCP
amnondanzig1724
anamikasarkar
apreconasia
aviralvatsa
David Orchard-Webb, PhD
danutdaagmailcom
Demet Sag, Ph.D., CRA, GCP
Dror Nir
evelinacohn
Gail S Thornton
Irina Robu
jdpmd
kellyperlman
Ed Kislauskis
larryhbern
lmulligan13gmailcom
marzankhan
megbaker58
pkandala
Rosalind Codrington, PhD
ritusaxena
Rick Mandahl
sjwilliamspa
stuartlpbi
Dr. Sudipta Saha
tildabarliya
zraviv06
zs22
Immunol Rev. 1999 Jun;169:195-207. Colitis in transgenic and knockout animals as models of human inflammatory bowel disease. Bhan AK 1, Mizoguchi E , Smith RN , Mizoguchi A . Author information Abstract
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 ” >