E-pharmacophore-based screening of mGluR5 negative allosteric modulators for central nervous system disorder. (February 2019)

• Record Type: Journal Article
• Authors: Vijaya Prabhu, Sitrarasu; Singh, Sanjeev Kumar
• Is Part Of: Computational biology and chemistry. Volume 78(2019)
• Page Start: 414
• Page End: 423
• Publication Date: 2019-02
• Subjects: Central nervous system -- E-pharmacophore -- mGluR5 -- Negative allosteric modulators -- Receiver operative characteristic -- Molecular dynamics simulations; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2018.12.016
• Languages: English
• ISSNs: 1476-9271

Abstract

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.