Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan.
Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan.
Bioorg Chem. 2020 Sep;102:104088. doi: 10.1016/j.bioorg.2020.104088. Epub 2020 Jul 12.
Alkaline phosphatases (APs) are a class of homodimeric enzymes which physiologically possess the dephosphorylation ability. APs catalyzes the hydrolysis of monoesters into phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are nitrogen and sulfur containing aromatic heterocycles considered as effective APs inhibitors. In this context, the current research paper presents the successful synthesis, spectroscopic characterization and in vitro alkaline phosphatase inhibitory potential of new thiazole derivatives. The structure activity relationship and molecular docking studies were performed to find out the binding modes of the screened compounds with the target site of tissue non-specific alkaline phosphatase (h-TNAP) as well as intestinal alkaline phosphatase (h-IAP). Compound 5e was found to be potent inhibitor of h-TNAP with IC value of 0.17 ± 0.01 µM. Additionally, compounds 5a and 5i were found to be highly selective toward h-TNAP with IC values of 0.25 ± 0.01 µM and 0.21 ± 0.02 µM, respectively. In case of h-IAP compound 5f was the most potent inhibitor with IC value of 1.33 ± 0.10 µM. The most active compounds were resort to molecular docking studies on h-TNAP and h-IAP to explore the possible binding interactions of enzyme-ligand complexes. Molecular dynamic simulations were carried out to investigate the overall stability of protein in apo and holo state.
碱性磷酸酶（APs）是一类同二聚体酶，在生理上具有去磷酸化能力。APs 催化单酯水解生成磷酸，进而催化磷酸转移反应。噻唑是一种含氮和硫的芳香杂环化合物，被认为是有效的 APs 抑制剂。在这种情况下，本研究论文介绍了新噻唑衍生物的成功合成、光谱表征和体外碱性磷酸酶抑制潜力。进行了结构活性关系和分子对接研究，以确定筛选化合物与组织非特异性碱性磷酸酶（h-TNAP）和肠碱性磷酸酶（h-IAP）靶位点的结合模式。发现化合物 5e 是 h-TNAP 的有效抑制剂，IC 值为 0.17±0.01µM。此外，化合物 5a 和 5i 对 h-TNAP 表现出高度选择性，IC 值分别为 0.25±0.01µM 和 0.21±0.02µM。对于 h-IAP，化合物 5f 是最有效的抑制剂，IC 值为 1.33±0.10µM。最活跃的化合物被用于 h-TNAP 和 h-IAP 的分子对接研究，以探索酶-配体复合物的可能结合相互作用。进行了分子动力学模拟，以研究apo 和 holo 状态下蛋白质的整体稳定性。
