E-pharmacophore-based screening of mGluR5 negative allosteric modulators for central nervous system disorder |
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| Institution: | 1. Department of Biotechnology, Alagappa University, Karaikudi 630003, Tamil Nadu, India;2. Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India;3. Computer Aided Drug Design and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi 630003, Tamil Nadu, India;1. School of Electrical and Information Engineering, Anhui University of Technology, 243032 Ma’anshan, Anhui, China;2. Institutes of Physical Science and Information Technology, Anhui University, 230601 Hefei, Anhui, China;1. Section of Pediatric Rheumatology, Department of Pediatrics, Medical College of Wisconsin, 8701 West Watertown Plank Road, Milwaukee, WI 53226, USA;2. Section of Hospital Medicine, Department of Pediatrics, Medical College of Wisconsin, 8701 West Watertown Plank Road, Milwaukee, WI 53226, USA;3. Department of Radiology, University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827, USA;4. Section of Pediatric Neurology, Department of Neurology, Medical College of Wisconsin, 8701 West Watertown Plank Road, Milwaukee, WI 53226, USA |
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| Abstract: | Glutamate, a major neurotransmitter in the central nervous system of human, plays a crucial role in various neurological pathways by activating the ligand-gated ion channels such as mGluR and iGluR. Dysfunction of mGluR 5 can cause Alzheimer’s disease, Parkinson’s disease, epilepsy, depression, anxiety, etc. In the current study, we have developed the energetically optimized pharmacophore model to screen the eMolecules database having more than 6 million compounds with the help of reported cocrystal structure with 3-chloro-5-6-(5-fluoropyridin-2 yl)pyrimidin-4-yl]benzonitrile (PDB ID: 5CGD). The obtained hits were docked into the allosteric site of the target and further validation of E-pharmacophore was done by enrichment calculations followed by the molecular dynamics simulations to analyze the specific amino acid interactions with the compound present in the allosteric site of the receptor. |
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| Keywords: | Central nervous system E-pharmacophore mGluR5 Negative allosteric modulators Receiver operative characteristic Molecular dynamics simulations |
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