Ligand supported homology modeling and docking evaluation of CCR2: docked pose selection by consensus scoring.
Summary of "Ligand supported homology modeling and docking evaluation of CCR2: docked pose selection by consensus scoring."
Chemokine receptor 2 (CCR2) is a G-protein coupled receptor (GPCR) and a crucial target for various inflammatory and autoimmune diseases. The structure based antagonists design for many GPCRs, including CCR2, is restricted by the lack of an experimental three dimensional structure. Homology modeling is widely used for the study of GPCR-ligand binding. Since there is substantial diversity for the ligand binding pocket and binding modes among GPCRs, the receptor-ligand binding mode predictions should be derived from homology modeling with supported ligand information. Thus, we modeled the binding of our proprietary CCR2 antagonist using ligand supported homology modeling followed by consensus scoring the docking evaluation based on all modeled binding sites. The protein-ligand model was then validated by visual inspection of receptor-ligand interaction for consistency of published site-directed mutagenesis data and virtual screening a decoy compound database. This model was able to successfully identify active compounds within the decoy database. Finally, additional hit compounds were identified through a docking-based virtual screening of a commercial database, followed by a biological assay to validate CCR2 inhibitory activity. Thus, this procedure can be employed to screen a large database of compounds to identify new CCR2 antagonists.
Affiliation
Department of Biotechnology, Yonsei University, Seoul, 120-749, Republic of Korea, jonghoon@yonsei.ac.kr.
Journal Details
This article was published in the following journal.
Name: Journal of molecular modeling
ISSN: 0948-5023
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21213000
- DOI: http://dx.doi.org/10.1007/s00894-010-0943-x
Medical and Biotech [MESH] Definitions
Sequence Homology
The degree of similarity between sequences. Studies of AMINO ACID SEQUENCE HOMOLOGY and NUCLEIC ACID SEQUENCE HOMOLOGY provide useful information about the genetic relatedness of genes, gene products, and species.
Evaluation Studies As Topic
Studies determining the effectiveness or value of processes, personnel, and equipment, or the material on conducting such studies. For drugs and devices, CLINICAL TRIALS AS TOPIC; DRUG EVALUATION; and DRUG EVALUATION, PRECLINICAL are available.
Tnf-related Apoptosis-inducing Ligand
A transmembrane-protein belonging to the TNF family of intercellular signaling proteins. It is a widely expressed ligand that activates APOPTOSIS by binding to TNF-RELATED APOPTOSIS-INDUCING LIGAND RECEPTORS. The membrane-bound form of the protein can be cleaved by specific CYSTEINE ENDOPEPTIDASES to form a soluble ligand form.
Structural Homology, Protein
The degree of 3-dimensional shape similarity between proteins. It can be an indication of distant AMINO ACID SEQUENCE HOMOLOGY and used for rational DRUG DESIGN.
Estrogen Receptor Beta
One of the ESTROGEN RECEPTORS that has greater affinity for ISOFLAVONES than ESTROGEN RECEPTOR ALPHA does. There is great sequence homology with ER alpha in the DNA-binding domain but not in the ligand binding and hinge domains.
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