Naushad Shaik Mohammad, Janaki Ramaiah M, Stanley Balraj Alex, Prasanna Lakshmi S, Vishnu Priya J, Hussain Tajamul, Alrokayan Salman A, Kutala Vijay Kumar
Sandor Life Sciences Pvt Ltd, Banjara Hills, Road No. 3, Hyderabad 500034, India; School of Chemical & Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur 613401, India.
School of Chemical & Biotechnology, SASTRA University, Tirumalaisamudram, Thanjavur 613401, India.
J Theor Biol. 2016 Oct 7;406:137-42. doi: 10.1016/j.jtbi.2016.07.016. Epub 2016 Jul 16.
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.
为开发一种对已报道的所有八种常见基因变体均有效的谷氨酸羧肽酶II（GCPII）潜在抑制剂，使用PyMOL分子可视化系统，以GCPII的晶体结构即2OOT为模板生成变体模型。对29种化合物进行的高通量虚拟筛选显示，这八种基因变体的药效存在差异（半数抑制浓度的负对数：4.70至10.22）。药效团分析和定量构效关系（QSAR）研究表明，一种基于尿素的N-乙酰天门冬氨酰谷氨酸（NAAG）类似物是更有效的抑制剂，GCPII的所有基因变体对其均有效，这一点通过Glide评分（-4.32至-7.08）和蛋白质-配体相互作用图（野生型GCPII中有13种相互作用）得到证明。该分子符合药物相似性的Lipinski五规则和三规则。作为一种NAAG类似物，该分子可能通过抑制由GCPII的剪接变体N-乙酰化α-连接酸性二肽酶（NAALADase）介导的谷氨酸能神经传递来提供神经保护作用。
