| Autor: |
Meira Menezes T; Fundamental Chemistry Department, Federal University of Pernambuco, Recife 50670-901, Brazil., Assis C; Department of Biochemistry and Physiology, Federal University of Pernambuco, Recife 50670-901, Brazil., Lacerda Cintra AJ; Department of Biochemistry and Physiology, Federal University of Pernambuco, Recife 50670-901, Brazil., Silva Dos Santos RC; Department of Education, Rural Federal University of Pernambuco, Recife 52171-900, Brazil., Martins do Vale WK; Department of Education, Rural Federal University of Pernambuco, Recife 52171-900, Brazil., Max Gomes Martins R; Post-Graduate in Biotechnology Multi-Institutional Program, PPGBIOTEC, Federal University of Amazonas, Manaus 69067-005, Brazil., de Souza Bezerra R; Department of Biochemistry and Physiology, Federal University of Pernambuco, Recife 50670-901, Brazil., Seabra GM; Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States., Li C; Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States., Neves JL; Fundamental Chemistry Department, Federal University of Pernambuco, Recife 50670-901, Brazil. |
| Abstrakt: |
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 5 M -1 . The obtained thermodynamic parameters reveal interactions driven by van der Waals forces and hydrogen bonds in the lapatinib-AChE system (Δ H ° and Δ S ° < 0). In contrast, the pazopanib-AChE system shows positive Δ H ° and Δ S °, 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. |
