Binding Mechanism between Acetylcholinesterase and Drugs Pazopanib and Lapatinib: Biochemical and Biophysical Studies

拉帕蒂尼 帕唑帕尼 化学 乙酰胆碱酯酶 药理学 生物化学 生物 医学 内科学 癌症 舒尼替尼 曲妥珠单抗 乳腺癌
作者
Thaís Meira Menezes,Caio Rodrigo Dias Assis,Alcides Jairon Lacerda Cintra,Roberto Carlos Silva dos Santos,Wilka Karla Martins do Vale,Regildo Max Gomes Martins,Ranilson de Souza Bezerra,Gustavo Seabra,Chenglong Li,Jorge Luiz Neves
出处
期刊:ACS Chemical Neuroscience [American Chemical Society]
卷期号:12 (24): 4500-4511 被引量:7
标识
DOI:10.1021/acschemneuro.1c00521
摘要

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 105 M-1. The obtained thermodynamic parameters reveal interactions driven by van der Waals forces and hydrogen bonds in the lapatinib-AChE system (ΔH° and ΔS° < 0). In contrast, the pazopanib-AChE system shows positive ΔH° and ΔS°, 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.
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