Document Detail

Targeting the BH3 domain mediated protein-protein interaction of Bcl-xL through virtual screening.
MedLine Citation:
PMID:  20392095     Owner:  NLM     Status:  MEDLINE    
Apoptosis, or programmed cell death, forms an important part of the cellular regulation machinery. The Bcl-2 protein family, comprising of proapoptotic and antiapoptotic members, forms an important part of the cells internal apoptotic pathway. Overexpression of the antiapoptotic members of the family in a number of cancer cell lines renders them immune to apoptosis and the ability to survive under conditions of cellular stress. Inhibition of the antiapoptotic members of the Bcl-2 family are, therefore, an interesting target for the development of anticancer therapy. An innovative structure-based virtual screening strategy was developed to identify inhibitors of Bcl-xL, an antiapoptotic member of the Bcl-2 family. Various innovative filters, such as receptor-based pharmacophore, cascade docking approach, cross-docking, and composite scoring with docking pose based descriptors were designed through exhaustive validation studies and implemented in the screening funnel. The 1.8 million 'big-n-greasy' subset from ZINC was screened using the protocol, and 45 compounds were finally selected for biological evaluation against Bcl-xL. The evaluation led to the identification of one low-micromolar and two weaker inhibitors belonging to novel scaffolds. Further evaluation of structure-activity relationships around these scaffolds could help in the development of anticancer leads against Bcl-xL.
Prasenjit Mukherjee; Prashant Desai; Yu-Dong Zhou; Mitchell Avery
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of chemical information and modeling     Volume:  50     ISSN:  1549-960X     ISO Abbreviation:  J Chem Inf Model     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-24     Completed Date:  2010-08-24     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101230060     Medline TA:  J Chem Inf Model     Country:  United States    
Other Details:
Languages:  eng     Pagination:  906-23     Citation Subset:  IM    
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
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MeSH Terms
Antineoplastic Agents / chemistry*,  pharmacology*
Binding Sites
Models, Molecular
Neoplasms / drug therapy
Protein Structure, Tertiary
Structure-Activity Relationship
bcl-X Protein / antagonists & inhibitors*,  chemistry,  metabolism*
Reg. No./Substance:
0/Antineoplastic Agents; 0/Ligands; 0/bcl-X Protein

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