In silico study of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanones derivatives as CCR1 antagonist: Homology modeling,docking and 3D-QSAR approach |
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| Affiliation: | 1. Department of Bio-New Drug Development, College of Medicine, Chosun University, Gwangju 501-759, Republic of Korea;2. Department of Cellular Molecular Medicine, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, Republic of Korea;1. Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan;2. Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan;1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2. Department of Laboratory Medicine, University of Washington, Seattle, WA, USA;3. Department of Microbiology, University of Washington, Seattle, WA, USA;4. Department of Biochemistry, University of Washington, Seattle, WA, USA;5. Department of Medicine, University of Washington, Seattle, WA, USA;3. Department of Biomedical Sciences, Texas A&M Health Science Center, Baylor College of Dentistry, Dallas, Texas 75246;4. Department of Medicine, University of Wisconsin, and Geriatric Research Education and Clinical Centers, Madison, Wisconsin 53705;1. Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia;2. Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia;3. P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy;4. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland;5. Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, POB 522, Mihaila Petrovica Alasa 14, 11001 Belgrade, Serbia;6. Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland |
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| Abstract: | C–C chemokine receptor type 1 (CCR1) is a chemokine receptor with seven transmembrane helices and it belongs to the G-Protein Coupled receptor (GPCR) family. It plays an important role in rheumatoid arthritis, organ transplant rejection, Alzheimer’s disease and also causes inflammation. Because of its role in disease processes, CCR1 is considered to be an important drug target. In the present study, we have performed three dimensional Quantitative Structure activity relationship (3D-QSAR) studies on a series of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanone derivatives targeting CCR1. Homology modeling of CCR1 was performed based on a template structure (4EA3) which has a high sequence identity and resolution. The highest active molecule was docked into this model. Ligand-based and Receptor-based quantitative structure–activity relationship (QSAR) study was performed and CoMFA models with reasonable statistics was developed for both ligand-based (q2 = 0.606; r2 = 0.968) and receptor-guided (q2 = 0.640; r2 = 0.932) alignment methods. Contour map analyses identified favorable regions for high affinity binding. The docking results highlighted the important active site residues. Tyr113 was found to interact with the ligand through hydrogen bonding. This residue has been considered responsible for anchoring ligands inside the active site. Our results could also be helpful to understand the inhibitory mechanism of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanone derivatives thereby to design more effective ligands in the future. |
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| Keywords: | CCR1 3D-QSAR Homology modeling Receptor-guided CoMFA Docking |
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