Fundamental Chemistry Department, Federal University of Pernambuco, Recife 50670-901, Brazil.
Department of Biochemistry and Physiology, Federal University of Pernambuco, Recife 50670-901, Brazil.
ACS Chem Neurosci. 2021 Dec 15;12(24):4500-4511. doi: 10.1021/acschemneuro.1c00521. Epub 2021 Nov 22.
Tyrosine kinase inhibitors (TKIs) are antitumor compounds that prevent the phosphorylation of proteins in a biological environment. However, the multitarget performance of TKIs promotes them as possible candidates for drug repositioning. In this work, interaction and inhibition studies through spectroscopic and computational techniques to evaluate the binding effectiveness of lapatinib and pazopanib TKIs to acetylcholinesterase (AChE) are reported. The results indicated potent inhibition at the μM level. The types of inhibition were identified, with pazopanib acting through non-competitive inhibition and lapatinib through acompetitive inhibition. The fluorescence suppression studies indicate a static mechanism for lapatinib-AChE and pazopanib-AChE systems, with a binding constant in the order of 10 M. The obtained thermodynamic parameters reveal interactions driven by van der Waals forces and hydrogen bonds in the lapatinib-AChE system (Δ° and Δ° < 0). In contrast, the pazopanib-AChE system shows positive Δ° and Δ°, characteristic of hydrophobic interactions. The Foster resonance energy transfer study supports the fluorescence studies performed. The 3D fluorescence studies suggest changes in the microenvironment of the tryptophan and tyrosine residues of the protein in contact with lapatinib and pazopanib. The results suggest effective inhibition and moderate interaction of the drugs with AChE, making them interesting for conducting more in-depth repositioning studies as AChE inhibitors.
酪氨酸激酶抑制剂（TKIs）是一类抗肿瘤化合物，可在生物环境中阻止蛋白质的磷酸化。然而，TKIs 的多靶点性能促使它们成为药物重定位的候选药物。在这项工作中，通过光谱和计算技术研究了 lapatinib 和 pazopanib TKIs 与乙酰胆碱酯酶（AChE）的相互作用和抑制作用，以评估其结合效力。结果表明，它们在微摩尔水平具有很强的抑制作用。确定了抑制类型，其中 pazopanib 通过非竞争性抑制起作用，而 lapatinib 通过竞争性抑制起作用。荧光猝灭研究表明 lapatinib-AChE 和 pazopanib-AChE 系统具有静态机制，结合常数在 10 M 左右。获得的热力学参数表明 lapatinib-AChE 系统中的相互作用是由范德华力和氢键驱动的（Δ°和Δ°<0）。相比之下，pazopanib-AChE 系统表现出正的Δ°和Δ°，这是疏水相互作用的特征。福斯特共振能量转移研究支持了所进行的荧光研究。3D 荧光研究表明与 lapatinib 和 pazopanib 接触的蛋白质色氨酸和酪氨酸残基的微环境发生了变化。结果表明，这些药物对 AChE 具有有效的抑制作用和适度的相互作用，这使得它们作为 AChE 抑制剂进行更深入的重定位研究很有意义。
