Studi Penambatan Molekuler Piperine sebagai Inhibitor Asetilkolinesterase (AChE) untuk Alzheimer
DOI:
https://doi.org/10.29313/bcsp.v6i2.24216Keywords:
Acetylcholinesterase, Penyakit Alzheimer, PiperinAbstract
Abstract. Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive impairment resulting from the degeneration of cholinergic neurons. Inhibition of acetylcholinesterase (AChE) remains one of the principal therapeutic strategies to preserve acetylcholine levels in the synaptic cleft and alleviate disease symptoms. Piperine, the major alkaloid compound found in Piper nigrum L., has demonstrated neuroprotective properties and is considered a promising natural compound for Alzheimer’s disease therapy. This study aimed to evaluate the binding potential of piperine toward AChE using a molecular docking approach. The three-dimensional structure of AChE (PDB ID: 2GYU) was obtained from the Protein Data Bank and prepared using BIOVIA Discovery Studio Visualizer. Docking protocol validation was carried out through a redocking procedure prior to molecular docking simulations performed with AutoDock Vina. The docking analysis revealed a binding affinity of –8.07 kcal/mol and an estimated inhibition constant (Ki) of 1.21 µM. Molecular interaction analysis indicated that piperine formed Carbon Hydrogen Bond, Pi-Donor Hydrogen Bond, Pi-Pi Stacked, Alkyl, and Pi-Alkyl interactions with amino acid residues located within the active site of AChE. These findings suggest that piperine exhibits favorable binding characteristics toward AChE and may serve as a potential acetylcholinesterase inhibitor. Nevertheless, further investigations, including molecular dynamics simulations as well as in vitro and in vivo studies, are required to validate the stability of the ligand–protein complex and its biological activity.
Abstrak.Penyakit Alzheimer merupakan gangguan neurodegeneratif progresif yang ditandai oleh penurunan fungsi kognitif akibat degenerasi neuron kolinergik. Salah satu pendekatan terapi yang banyak diterapkan untuk mengurangi gejala penyakit ini adalah menghambat aktivitas enzim asetilkolinesterase (AChE), sehingga kadar asetilkolin di celah sinaps dapat dipertahankan. Piperin, senyawa alkaloid utama yang terdapat pada Piper nigrum L., diketahui memiliki aktivitas neuroprotektif dan berpotensi dikembangkan sebagai kandidat inhibitor AChE. Penelitian ini bertujuan mengevaluasi kemampuan piperin dalam berikatan dengan enzim AChE menggunakan pendekatan molecular docking. Struktur tiga dimensi protein target (PDB ID: 2GYU) diperoleh dari Protein Data Bank dan dipreparasi menggunakan BIOVIA Discovery Studio Visualizer. Validasi metode dilakukan melalui proses redocking, kemudian dilanjutkan dengan simulasi docking menggunakan AutoDock Vina. Hasil simulasi menunjukkan bahwa piperin memiliki nilai binding affinity sebesar –8,07 kcal/mol dengan nilai inhibition constant (Ki) sebesar 1,21 µM. Analisis interaksi molekuler memperlihatkan terbentuknya interaksi Carbon Hydrogen Bond, Pi-Donor Hydrogen Bond, Pi-Pi Stacked, Alkyl, dan Pi-Alkyl dengan residu asam amino pada sisi aktif AChE. Temuan tersebut menunjukkan bahwa piperin mampu berikatan secara stabil dengan protein target dan berpotensi dikembangkan sebagai kandidat inhibitor asetilkolinesterase. Meskipun demikian, diperlukan penelitian lanjutan melalui simulasi molecular dynamics serta pengujian in vitro dan in vivo untuk mengonfirmasi kestabilan kompleks dan aktivitas biologisnya.
References
Bhat, B. A., Almilaibary, A., Mir, R. A., Aljarallah, B. M., Mir, W. R., Ahmad, F., & Mir, M. A. (2022). Natural Therapeutics in Aid of Treating Alzheimer’s Disease: A Green Gateway Toward Ending Quest for Treating Neurological Disorders. Frontiers in Neuroscience, 16. https://doi.org/10.3389/fnins.2022.884345
Lalu Sanik Wahyu Fadil Amrulloh, Nuraini Harmastuti, Andri Prasetiyo, & Rina Herowati. (2023). Analysis of Molecular Docking and Dynamics Simulation of Mahogany (Swietenia macrophylla King) Compounds Against the PLpro Enzyme SARS-COV-2. JURNAL FARMASI DAN ILMU KEFARMASIAN INDONESIA, 10(3), 347–359. https://doi.org/10.20473/jfiki.v10i32023.347-359
Meng, X.-Y., Zhang, H.-X., Mezei, M., & Cui, M. (2011). Molecular Docking: A Powerful Approach for Structure-Based Drug Discovery. Current Computer Aided-Drug Design, 7(2), 146–157. https://doi.org/10.2174/157340911795677602
Munazzah Tasleem, Ambreen Shoaib, Asma Al-Shammary, Abdelmuhsin Abdelgadir, Zeina Alsamar, Qazi Mohammad Sajid Jamal, Abdulwahed Alrehaily, Fevzi Bardcki, Abdel Moneim E. Sulieman, Tarun Kumar Upadhyay, Irfan Ahmad Ansari, Dakun Lai, Riadh Badroui, Dharmendra Kumar Yadav, & Mohd Saeed. (2022). Computational analysis of PTP-1B site-directed mutations and their structural binding to potential inhibitors. Cellular and Molecular Biology, 68(7), 75–84. https://doi.org/10.14715/cmb/2022.68.7.13
Peitzika, S.-C., & Pontiki, E. (2023). A Review on Recent Approaches on Molecular Docking Studies of Novel Compounds Targeting Acetylcholinesterase in Alzheimer Disease. Molecules, 28(3), 1084. https://doi.org/10.3390/molecules28031084
Prasetiawati, R. (2022). Studi Penambatan Molekul Senyawa Turunan Fenilpropanoid Pada Tumbuhan Lengkuas (Alpina galangal (L.) Willd.) Sebagai Obat Antikanker Otak. Parapemikir : Jurnal Ilmiah Farmasi, 11(2), 189. https://doi.org/10.30591/pjif.v11i2.2919
S. Figueredo, A., G. de Oliveira, M., M.V.V. Safadi, G., de Paula da Silva, C. H. T., B. da Silva, V., A. Taft, C., & L. B. de Aquino, G. (2016). The Natural Alkaloid Piperine and its Acid and Ester Synthetic Derivatives are Acetylcholinesterase Inhibitors. Current Physical Chemistry, 5(4), 294–300. https://doi.org/10.2174/187794680504160308115710
Son, M., Park, C., Rampogu, S., Zeb, A., & Lee, K. W. (2019). Discovery of Novel Acetylcholinesterase Inhibitors as Potential Candidates for the Treatment of Alzheimer’s Disease. International Journal of Molecular Sciences, 20(4), 1000. https://doi.org/10.3390/ijms20041000
Varma, A. K., Patil, R., Das, S., Stanley, A., Yadav, L., & Sudhakar, A. (2010). Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of Drug-Designing. PLoS ONE, 5(8). https://doi.org/10.1371/journal.pone.0012029
Zuliani, G., Zuin, M., Romagnoli, T., Polastri, M., Cervellati, C., & Brombo, G. (2024). Acetyl-cholinesterase-inhibitors reconsidered. A narrative review of post-marketing studies on Alzheimer’s disease. Aging Clinical and Experimental Research, 36(1), 23. https://doi.org/10.1007/s40520-023-02675-6
