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)

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.

Keywords:

autism , Drug design , Molecular docking , Molecular Simulation , potassium channel , Zonisamide