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Characterization of the interactions between coumarin-derivatives and acetylcholinesterase: Examination by NMR and docking simulations

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Abstract

Alzheimer’s disease (AD) is one of the most common forms of dementia and a significant threat to the elderly populations, especially in the Western world. The rapid hydrolysis of the principal neurotransmitter into choline and acetate by acetylcholinesterase (AChE) at synapses causes the loss of cognitive response that becomes the real cause of AD. Therefore, inhibition of AChE is the most fundamental therapy among currently available treatments for AD. In this context, we designed and performed molecular recognitions studies of coumarin-based inhibitors towards AChE. STD NMR and Tr-NOESY applications were utilized to evaluate the binding epitope, the dissociation constant (KD) and bound conformations of these inhibitors within this inhibitor-AChE complex. Compound 1, which has a similar inhibition activity to tacrine (a current drug) led in this study as a stronger binder with KD = 30 μM ,even greater than tacrine (KD = 140 μM). Moreover, docking simulations mimic NMR results and provided evidence of synchronizing binding of compound 1 with three sites; the peripheral anionic site, the bottom of the gorge, and the catalytic site. Therefore, we envisioned from our experimental and theoretical results that coumarin-based inhibitors containing a piperidinyl scaffold might be a potential drug candidates for AD in the future.

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Acknowledgments

The authors of the manuscript are thankful for and gratefully acknowledge the financial support from the World Acaemy of Sciences/National Council for Scientific and Technological Development (TWAS/CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Brazilian funding agency.

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Authors and Affiliations

  1. Department of Metallurgy and Materials Engneering, Pakistan Institute of Engineering and Applied Sciences (PIEAS), Lehtrar Road, Nilore, Islamabad, 45650, Pakistan

    Nazish U. Tanoli & Mazhar Mehmood

  2. Laboratory of Nuclear Magnetic Resonance, Federal University of São Carlos, Rodovia Washington Luiz, Km 235, São Carlos, SP, 13565-905, Brazil

    Nazish U. Tanoli, Sheraz A. K. Tanoli, Antonio G. Ferreira & Tiago Venâncio

  3. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemicals and Biological Sciences, University of Karachi, Karachi, 75210, Pakistan

    Sana Gul & Zaheer Ul-Haq

  4. Laboratory of Synthesis of Natural Products, Department of Chemistry, Federal University of São Carlos, São Carlos, SP, 13565-905, Brazil

    Julia L. Monteiro, Lucas C. C. Vieira & Arlene G. Correa

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  1. Nazish U. Tanoli
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  2. Sheraz A. K. Tanoli
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Correspondence to Nazish U. Tanoli or Sheraz A. K. Tanoli.

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Tanoli, N.U., Tanoli, S.A.K., Ferreira, A.G. et al. Characterization of the interactions between coumarin-derivatives and acetylcholinesterase: Examination by NMR and docking simulations. J Mol Model 24, 207 (2018). https://doi.org/10.1007/s00894-018-3751-3

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  • DOI: https://doi.org/10.1007/s00894-018-3751-3

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