In silico approaches to identify the potential inhibitors of glutamate carboxypeptidase II (GCPII) for neuroprotection. (7th October 2016)

• Record Type: Journal Article
• Authors: Naushad, Shaik Mohammad; Janaki Ramaiah, M.; Stanley, Balraj Alex; Prasanna Lakshmi, S.; Vishnu Priya, J.; Hussain, Tajamul; Alrokayan, Salman A.; Kutala, Vijay Kumar
• Is Part Of: Journal of theoretical biology. Volume 406(2016)
• Page Start: 137
• Page End: 142
• Publication Date: 2016-10-07
• Subjects: Glutamate carboxypeptidase II -- N-acetyl aspartyl glutamate -- Glutamatergic transmission -- Urea-based NAAG-analogue; Biology -- Periodicals; Biological Science Disciplines -- Periodicals; Biology -- Periodicals; Biologie -- Périodiques; Theoretische biologie; Biology; Periodicals; 571.05
• DOI: 10.1016/j.jtbi.2016.07.016
• Languages: English
• ISSNs: 0022-5193

Abstract

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 . Highlights: GCPII inhibition neuroprotective. Urea-based NAAG analogue exhibited potential inhibition across all GCPII variants. This lead molecule exhibited strong interactions with both the active Zinc ions. It satisfied both the Lipinski rule of five and rule of three for drug-likeliness.