Structure-activity and binding orientations analysis of potent, newly synthesized, acetylcholinesterase inhibitors
Samo za registrovane korisnike
2023
Autori
Krunić, MihajloPenjišević, Jelena
Suručić, Relja
Šegan, Sandra
Kostić-Rajačić, Slađana
Jevtić, Ivana
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
Fourteen novel N-benzylpiperidine and N,N-diarylpiperazine conjugates were synthesized and pharmacologically evaluated as donepezil analogs, in a ligand-based drug design approach. All compounds possessed high to moderate in vitro inhibitory activity with IC50 in range 2.3–20 µM and selectivity towards acetylcholinesterase, while being inactive towards butyrylcholinesterase. Structure-activity relationship analysis revealed the influence of N,N-diarylpiperazine moiety and the linker connecting two pharmacophores on the inhibitory activity. Kinetic studies on the two most active compounds 7g and 8g (IC50 = 2.3 and 4 µM, respectively) revealed mixed type mode of inhibition, binding to both, free enzyme and enzyme-substrate complex. For further understanding of mechanism of action and binding orientations, molecular docking was performed for all compounds, while the ligand transport simulation and molecular dynamics simulations were performed for 7g and 8g. Computational results corrobora...ted well with in vitro activities and kinetic studies.
Ključne reči:
Alzheimer's disease / Arylpiperazine / Cholinesterase / Ligand transport simulation / Molecular docking / Molecular dynamics / N-benzylpiperidineIzvor:
Journal of Molecular Structure, 2023, 1276, 134809-Izdavač:
- Elsevier B.V.
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200026 (Univerzitet u Beogradu, Institut za hemiju, tehnologiju i metalurgiju - IHTM) (RS-MESTD-inst-2020-200026)
DOI: 10.1016/j.molstruc.2022.134809
ISSN: 0022-2860; 1872-8014
WoS: 000904118100004
Scopus: 2-s2.0-85145591644
Institucija/grupa
IHTMTY - JOUR AU - Krunić, Mihajlo AU - Penjišević, Jelena AU - Suručić, Relja AU - Šegan, Sandra AU - Kostić-Rajačić, Slađana AU - Jevtić, Ivana PY - 2023 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/5634 AB - Fourteen novel N-benzylpiperidine and N,N-diarylpiperazine conjugates were synthesized and pharmacologically evaluated as donepezil analogs, in a ligand-based drug design approach. All compounds possessed high to moderate in vitro inhibitory activity with IC50 in range 2.3–20 µM and selectivity towards acetylcholinesterase, while being inactive towards butyrylcholinesterase. Structure-activity relationship analysis revealed the influence of N,N-diarylpiperazine moiety and the linker connecting two pharmacophores on the inhibitory activity. Kinetic studies on the two most active compounds 7g and 8g (IC50 = 2.3 and 4 µM, respectively) revealed mixed type mode of inhibition, binding to both, free enzyme and enzyme-substrate complex. For further understanding of mechanism of action and binding orientations, molecular docking was performed for all compounds, while the ligand transport simulation and molecular dynamics simulations were performed for 7g and 8g. Computational results corroborated well with in vitro activities and kinetic studies. PB - Elsevier B.V. T2 - Journal of Molecular Structure T1 - Structure-activity and binding orientations analysis of potent, newly synthesized, acetylcholinesterase inhibitors VL - 1276 SP - 134809 DO - 10.1016/j.molstruc.2022.134809 ER -
@article{ author = "Krunić, Mihajlo and Penjišević, Jelena and Suručić, Relja and Šegan, Sandra and Kostić-Rajačić, Slađana and Jevtić, Ivana", year = "2023", abstract = "Fourteen novel N-benzylpiperidine and N,N-diarylpiperazine conjugates were synthesized and pharmacologically evaluated as donepezil analogs, in a ligand-based drug design approach. All compounds possessed high to moderate in vitro inhibitory activity with IC50 in range 2.3–20 µM and selectivity towards acetylcholinesterase, while being inactive towards butyrylcholinesterase. Structure-activity relationship analysis revealed the influence of N,N-diarylpiperazine moiety and the linker connecting two pharmacophores on the inhibitory activity. Kinetic studies on the two most active compounds 7g and 8g (IC50 = 2.3 and 4 µM, respectively) revealed mixed type mode of inhibition, binding to both, free enzyme and enzyme-substrate complex. For further understanding of mechanism of action and binding orientations, molecular docking was performed for all compounds, while the ligand transport simulation and molecular dynamics simulations were performed for 7g and 8g. Computational results corroborated well with in vitro activities and kinetic studies.", publisher = "Elsevier B.V.", journal = "Journal of Molecular Structure", title = "Structure-activity and binding orientations analysis of potent, newly synthesized, acetylcholinesterase inhibitors", volume = "1276", pages = "134809", doi = "10.1016/j.molstruc.2022.134809" }
Krunić, M., Penjišević, J., Suručić, R., Šegan, S., Kostić-Rajačić, S.,& Jevtić, I.. (2023). Structure-activity and binding orientations analysis of potent, newly synthesized, acetylcholinesterase inhibitors. in Journal of Molecular Structure Elsevier B.V.., 1276, 134809. https://doi.org/10.1016/j.molstruc.2022.134809
Krunić M, Penjišević J, Suručić R, Šegan S, Kostić-Rajačić S, Jevtić I. Structure-activity and binding orientations analysis of potent, newly synthesized, acetylcholinesterase inhibitors. in Journal of Molecular Structure. 2023;1276:134809. doi:10.1016/j.molstruc.2022.134809 .
Krunić, Mihajlo, Penjišević, Jelena, Suručić, Relja, Šegan, Sandra, Kostić-Rajačić, Slađana, Jevtić, Ivana, "Structure-activity and binding orientations analysis of potent, newly synthesized, acetylcholinesterase inhibitors" in Journal of Molecular Structure, 1276 (2023):134809, https://doi.org/10.1016/j.molstruc.2022.134809 . .