| Autor: |
de Almeida RBM; Department of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, Brazil., Barbosa DB; Department of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, Brazil., do Bomfim MR; Department of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, Brazil., Amparo JAO; Institute of Health Sciences, Federal University of Bahia, Salvador 40170-110, BA, Brazil., Andrade BS; Department of Biological Sciences, State University of Southwest of Bahia, Jequié 45208-091, BA, Brazil., Costa SL; Institute of Health Sciences, Federal University of Bahia, Salvador 40170-110, BA, Brazil., Campos JM; Biosanitary Institute of Granada (ibs.GRANADA), University of Granada, 18071 Granada, Spain.; Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, University of Granada, 18071 Granada, Spain., Cruz JN; Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil., Santos CBR; Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, University of Granada, 18071 Granada, Spain.; Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil., Leite FHA; Department of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, Brazil., Botura MB; Department of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, Brazil. |
| Abstrakt: |
The enhancement of cholinergic functions via acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition is considered a valuable therapeutic strategy for the treatment of Alzheimer's disease. This study aimed to evaluate the in vitro effect of ZINC390718, previously filtered using computational approaches, on both cholinesterases and to characterize, using a molecular dynamics (MD) simulation, the possible binding mode of this compound inside the cholinesterase enzymes. The in vitro cytotoxicity effect was also investigated using a primary astrocyte-enriched glial cell culture. ZINC390718 presented in vitro dual inhibitory activity against AChE at a high micromolar range (IC 50 = 543.8 µM) and against BuChE (IC 50 = 241.1 µM) in a concentration-dependent manner, with greater activity against BuChE. The MD simulation revealed that ZINC390718 performed important hydrophobic and H-bond interactions with the catalytic residue sites on both targets. The residues that promoted the hydrophobic interactions and H-bonding in the AChE target were Leu67, Trp86, Phe123, Tyr124, Ser293, Phe295, and Tyr341, and on the BuChE target, they were Asp70, Tyr332, Tyr128, Ile442, Trp82, and Glu197. The cytotoxic effect of Z390718, evaluated via cell viability, showed that the molecule has low in vitro toxicity. The in vitro and in silico results indicate that ZINC390718 can be used as chemotype for the optimization and identification of new dual cholinesterase inhibitors. |
