CC chemokine receptor 2 (CCR2) antagonists that disrupt CCR2/MCP-1 interaction are expected to treat a variety of inflammatory and autoimmune diseases. The lack of CCR2 crystal structure limits the application of structure-based drug design (SBDD) to this target. Although a few three-dimensional theoretical models have been reported, their accuracy remains to be improved in terms of templates and modeling approaches. In this study, we developed a unique ligand-steered strategy for CCR2 homology modeling. It starts with an initial model based on the X-ray structure of the closest homolog so far, that is, CXCR4. Then, it uses Elastic Network Normal Mode Analysis (EN-NMA) and flexible docking (FD) by AutoDock Vina software to generate ligand-induced fit models. It selects optimal model(s) as well as scoring function(s) via extensive evaluation of model performance based on a unique benchmarking set constructed by our in-house tool, that is, MUBD-DecoyMaker. The model of 81_04 presents the optimal enrichment when combined with the scoring function of PMF04, and the proposed binding mode between CCR2 and Teijin lead by this model complies with the reported mutagenesis data.Bak Antibody Data Sheet To highlight the advantage of our strategy, we compared it with the only reported ligand-steered strategy for CCR2 homology modeling, that is, Discovery Studio/Ligand Minimization.CYP3A4 Antibody Purity & Documentation Lastly, we performed prospective virtual screening based on 81_04 and CCR2 antagonist bioassay.PMID:34849851 The identification of two hit compounds, that is, E859-1281 and MolPort-007-767-945, validated the efficacy of our model and the ligand-steered strategy.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2021 The Authors. Chemical Biology & Drug Design published by John Wiley & Sons Ltd 944
wileyonlinelibrary.com/journal/cbdd
Chem Biol Drug Des. 2021;97:944–961.
JIN et al.
KEYWORDS
CCR2, flexible docking, ligand-steered homology modeling, MUBD-DecoyMaker, normal mode analysis, structure-based virtual screeningMedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
