Document Detail

Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach.
MedLine Citation:
PMID:  20960031     Owner:  NLM     Status:  MEDLINE    
CXCR4 is a G-protein coupled receptor for CXCL12 that plays an important role in human immunodeficiency virus infection, cancer growth and metastasization, immune cell trafficking and WHIM syndrome. In the absence of an X-ray crystal structure, theoretical modeling of the CXCR4 receptor remains an important tool for structure-function analysis and to guide the discovery of new antagonists with potential clinical use. In this study, the combination of experimental data and molecular modeling approaches allowed the development of optimized ligand-receptor models useful for elucidation of the molecular determinants of small molecule binding and functional antagonism. The ligand-guided homology modeling approach used in this study explicitly re-shaped the CXCR4 binding pocket in order to improve discrimination between known CXCR4 antagonists and random decoys. Refinement based on multiple test-sets with small compounds from single chemotypes provided the best early enrichment performance. These results provide an important tool for structure-based drug design and virtual ligand screening of new CXCR4 antagonists.
Marco A C Neves; Sérgio Simões; M Luisa Sá e Melo
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-20
Journal Detail:
Title:  Journal of computer-aided molecular design     Volume:  24     ISSN:  1573-4951     ISO Abbreviation:  J. Comput. Aided Mol. Des.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-22     Completed Date:  2011-03-14     Revised Date:  2013-08-12    
Medline Journal Info:
Nlm Unique ID:  8710425     Medline TA:  J Comput Aided Mol Des     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1023-33     Citation Subset:  IM    
Centro de Estudos Farmacêuticos, Laboratório de Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, Pólo das Ciências da Saúde, Coimbra, Portugal.
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MeSH Terms
Artificial Intelligence
Binding Sites
Computer Simulation
Crystallography, X-Ray
Drug Design*
Heterocyclic Compounds / chemistry
Heterocyclic Compounds, 1-Ring / chemistry
Models, Molecular
Protein Binding
Pyridines / chemistry
Receptors, Adrenergic, beta-2 / chemistry
Receptors, CXCR4 / antagonists & inhibitors*,  chemistry*
Sequence Alignment
Sequence Homology, Amino Acid
Structural Homology, Protein*
Structure-Activity Relationship
Reg. No./Substance:
0/CXCR4 protein, human; 0/Heterocyclic Compounds; 0/Heterocyclic Compounds, 1-Ring; 0/Ligands; 0/N'-((1H-benzo(d)imidazol-2-yl)methyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine; 0/N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; 0/Pyridines; 0/Receptors, Adrenergic, beta-2; 0/Receptors, CXCR4; 155148-31-5/JM 3100

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