Evaluation of Medicinal Effects of Isoxazole Ring Isosteres on Zonisamide for Autism Treatment by Binding to Potassium Voltage-Gated Channel Subfamily D Member 2 (Kv 4.2)

M. Nabati, Vida Bodaghi-Namileh
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引用次数: 5

Abstract

The present research study discusses discovery of the novel drugs based on Zonisamide (FDA-approved drug) to treat the autism disease. We designed novel compounds by changing the pyrazole ring of the molecular structure with its isosteric rings. The main goal of the present study is evaluation of isosterism effect on Zonisamide compound. The studied pyrazole isosters are isothiazole, [c] azaphosphole, [d] azaphosphole, oxaphosphole, thiaphosphole and diphosphole. First, all designed molecular structures were optimized using density functional theory (DFT) computational method by B3LYP/6-311++G(d,p) basis set of theory. All the computations were performed in isolated form at room temperature. Then, making complex of all optimized molecular structures with A-type potassium voltage gated subfamily d member 2 (Kv 4.2) was studied. The ligand-receptor complexes energy data showed all designed molecules except (1H-indazol-3-yl)methanesulfonamide interct with channel weakly. The residues Phe 75, Asp 86, Phe 84, and Phe 74 played main role in making complex with (1H-indazol-3-yl)methanesulfonamide. However, the ADME and biological properties of the designed molecules were carried out using swissADME and FAF-Drugs4 web tools. Based on the ligand-channel complexes docking data and biochemical properties of the compounds, the pyrazole pentet ring is a suitable isostere for isoxazole ring in Zonisamide.
通过结合钾电压门控通道亚家族D成员2 (Kv 4.2)评价异恶唑环异构体对唑尼沙胺治疗自闭症的疗效
本研究探讨了以唑尼沙胺(fda批准的药物)为基础的治疗自闭症的新药的发现。我们通过将分子结构中的吡唑环改为等构环来设计新的化合物。本研究的主要目的是评价唑尼沙胺化合物的等构效应。所研究的吡唑同分异构体有异噻唑、[c]氮磷孔、[d]氮磷孔、草磷孔、硫磷孔和二磷孔。首先,采用B3LYP/6-311++G(d,p)基理论集的密度泛函理论(DFT)计算方法对所有设计的分子结构进行优化。所有计算均在室温下以孤立形式进行。然后,研究了所有优化分子结构与a型钾电压门控亚族d成员2 (Kv 4.2)的配合物。配体-受体配合物的能量数据表明,除(1h -茚唑-3-酰基)甲磺酰胺外,设计的分子与通道的相互作用较弱。氨基酸残基Phe 75、Asp 86、Phe 84和Phe 74在与(1h -吲哚-3-酰基)甲磺酰胺络合物的合成中起主要作用。然而,设计的分子的ADME和生物学特性是使用swissADME和FAF-Drugs4网络工具进行的。根据配体-通道配合物对接数据和化合物的生化性质,吡唑五环是唑尼沙胺中异恶唑环的合适异构体。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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