Abstract

The present manuscript describes the synthesis, α-amylase inhibition, in silico studies and in-depth quantitative structure–activity relationship (QSAR) of a library of aroyl hydrazones based on benzothiazole skeleton. All the compounds of the developed library are characterized by various spectral techniques. α‐Amylase inhibitory potential of all compounds has been explored, where compound 7n exhibits remarkable α-amylase inhibition of 87.5% at 50 µg/mL. Robust QSAR models are made by using the balance of correlation method in CORAL software. The chemical structures at different concentration with optimal descriptors are represented by SMILES. A data set of 66 SMILES of 22 hydrazones at three distinct concentrations are prepared. The significance of the index of ideality of correlation (IIC) with applicability domain (AD) is also studied at depth. A QSAR model with best $R_{\mathit{validation}}^2$ = 0.8587 for split 1 is considered as a leading model. The outliers and promoters of increase and decrease of endpoint are also extracted. The binding modes of the most active compound, that is, 7n in the active site of Aspergillus oryzae α-amylase (PDB ID: 7TAA) are also explored by in silico molecular docking studies. Compound 7n displays high resemblance in binding mode and pose with the standard drug acarbose. Molecular dynamics simulations performed on protein–ligand complex for 100 ns, the protein gets stabilised after 20 ns and remained below 2 Å for the remaining simulation. Moreover, the deviation observed in RMSF during simulation for each amino acid residue with respect to Cα carbon atom is insignificant.

摘要

本手稿描述了基于苯并噻唑骨架的芳酰腙文库的合成、α-淀粉酶抑制、计算机研究和深入的定量构效关系 (QSAR)。开发库中的所有化合物都通过各种光谱技术进行了表征。已经探索了所有化合物的α-淀粉酶抑制潜力，其中化合物7n表现出显着的α-淀粉酶抑制在 50 µg/mL 时为 87.5%。利用CORAL软件中的相关平衡法建立了稳健的QSAR模型。具有最佳描述符的不同浓度的化学结构由 SMILES 表示。准备了三个不同浓度的 22 个腙的 66 个 SMILES 数据集。还深入研究了相关理想指数 (IIC) 与适用域 (AD) 的重要性。最佳 QSAR 模型$R_{\mathit{验证}}^2$ = 0.8587 for split 1 被认为是领先的模型。还提取了端点增加和减少的异常值和启动子。最活跃的化合物，即7n在米曲霉α-淀粉酶 ( PDB ID: 7TAA ) 活性位点的结合模式也通过计算机分子对接研究进行了探索。复合7n与标准药物阿卡波糖在结合模式和姿势上表现出高度相似性。对蛋白质-配体复合物进行 100 ns 的分子动力学模拟，蛋白质在 20 ns 后稳定，并在剩余的模拟中保持在 2 Å 以下。此外，在模拟过程中每个氨基酸残基相对于 Cα 碳原子在 RMSF 中观察到的偏差是微不足道的。