posted on 2021-11-22, 23:03authored byThaís Meira Menezes, Caio Assis, Alcides Jairon Lacerda Cintra, Roberto Carlos Silva dos Santos, Wilka Karla Martins do Vale, Regildo Max Gomes Martins, Ranilson de Souza Bezerra, Gustavo de Miranda Seabra, Chenglong Li, Jorge Luiz Neves
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.