title: In silico approaches to identify the potential inhibitors of glutamate carboxypeptidase II (GCPII) for neuroprotection.
abstract: To develop a potential inhibitor for glutamate carboxypeptidase II (GCPII) effective against all the eight common genetic variants reported, PyMOL molecular visualization system was used to generate models of variants using the crystal structure of GCPII i.e. 2OOT as a template. High-throughput virtual screening of 29 compounds revealed differential efficacy across the eight genetic variants (pIC50: 4.70 to 10.22). Pharmacophore analysis and quantitative structure-activity relationship (QSAR) studies revealed a urea-based N-acetyl aspartyl glutamate (NAAG) analogue as more potent inhibitor, which was effective across all the genetic variants of GCPII as evidenced by glide scores (-4.32 to -7.08) and protein-ligand interaction plots (13 interactions in wild GCPII). This molecule satisfied Lipinski rule of five and rule of three for drug-likeliness. Being a NAAG-analogue, this molecule might confer neuroprotection by inhibiting glutamatergic neurotransmission mediated by N-acetylated alpha-linked acidic dipeptidase (NAALADase), a splice variant of GCPII.
authors.affiliation: Sandor Life Sciences Pvt Ltd, Banjara Hills, Road No. 3, Hyderabad 500034, India; School of Chemical & Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur 613401, India. Electronic address: naushadsm@gmail.com.
authors.forename: Shaik Mohammad
authors.initials: SM
authors.lastname: Naushad
authors.affiliation: School of Chemical & Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur 613401, India.
authors.forename: M
authors.initials: M
authors.lastname: Janaki Ramaiah
authors.affiliation: School of Chemical & Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur 613401, India.
authors.forename: Balraj Alex
authors.initials: BA
authors.lastname: Stanley
authors.affiliation: School of Chemical & Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur 613401, India.
authors.forename: S
authors.initials: S
authors.lastname: Prasanna Lakshmi
authors.affiliation: School of Chemical & Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur 613401, India.
authors.forename: J
authors.initials: J
authors.lastname: Vishnu Priya
authors.affiliation: Center of Excellence in Biotechnology Research & College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Tajamul
authors.initials: T
authors.lastname: Hussain
authors.affiliation: Department of Biochemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Salman A
authors.initials: SA
authors.lastname: Alrokayan
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad 500082, India.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
mesh_terms: D003198:Computer Simulation; D014644:Genetic Variation; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D000066829:Neuroprotection / Q000187:drug effects*; D011480:Protease Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D043425:Glutamate Carboxypeptidase II
keywords: Glutamate carboxypeptidase II; Glutamatergic transmission; N-acetyl aspartyl glutamate; Urea-based NAAG-analogue