Targeting Dopamine Transporter (DAT) with Peronema canescens Bioactives: A Molecular Docking Study for Stroke-Related Pain and Sedation Management
DOI:
https://doi.org/10.33751/helium.v5i1.19Kata Kunci:
Dopamine Transporter (DAT), Molecular Docking, Neuropharmacology, Peronema canescens, Stroke-Related PainAbstrak
Pain and drowsiness are common symptoms of stroke recovery, which can be difficult to manage owing to neurochemical abnormalities in the dopamine system. The Dopamine Transporter (DAT) controls dopamine levels, which influences pain perception and neurological recovery. This study examines bioactive chemicals found in Peronema canescens leaves and their possible interactions with DAT. AutoDock Vina was used to perform molecular docking simulations to determine the binding affinities of Peronemin derivatives (A2, A3, and B2) to the Dopamine Transporter (DAT). The receptor structure (PDB ID: 4M48) was created by eliminating water molecules, introducing polar hydrogens, and optimizing the structure using AutoDockTools. Ligand structures were translated to the proper format, and docking was conducted using a grid box centered on DAT's active site, with an exhaustiveness value of 10. The Peronemin derivatives A2, A3, and B2 demonstrated binding affinities stronger than nortriptyline, native ligand (−10.6, −10.5, and −10.3 kcal/mol, respectively) and binding similarities ranging from 72.2% to 94.4%. These findings suggest that Peronema canescens bioactives may be promising candidates for stroke-related pain and sedative control, warranting further experimental validation.
Referensi
V. L. Feigin et al., "Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019," The Lancet Neurology, vol. 20, no. 10, pp. 795-820, 2021.
B. S. Haslam, D. S. Butler, A. S. Kim, and L. M. Carey, "Chronic pain following stroke: current treatment and perceived effect," Disability and Health Journal, vol. 14, no. 1, p. 100971, 2021.
D. Frank, B. F. Gruenbaum, A. Zlotnik, M. Semyonov, A. Frenkel, and M. Boyko, "Pathophysiology and current drug treatments for post-stroke depression: a review," International Journal of Molecular Sciences, vol. 23, no. 23, p. 15114, 2022.
P. C. McHugh and D. A. Buckley, "The structure and function of the dopamine transporter and its role in CNS diseases,"Vitamins & Hormones, vol. 98, pp. 339- 369, 2015.
M. Linnerbauer, M. A. Wheeler, and F. J. Quintana, "Astrocyte crosstalk in CNS inflammation," Neuron, vol. 108, no. 4, pp. 608-622, 2020.
R. Costa, N. G. Oliveira, and R. J. Dinis- Oliveira, "Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects," Drug metabolism reviews, vol. 51, no. 3, pp. 293-313, 2019.
J.-J. Ang, B.-S. Low, and P.-F. Wong, "Dopamine and central dopaminergic circuitry in neurodegenerative diseases: Roles and mechanisms of action of natural phytochemicals," Pharmacological Research-Natural Products, p. 100050, 2024.
A. H. Ahkam, Y. Susilawati, and S. A. Sumiwi, "Peronema canescens as a Source of Immunomodulatory Agents: A New Opportunity and Perspective," Biology, vol. 13, no. 9, p. 744, 2024.
X.-Y. Meng, H.-X. Zhang, M. Mezei, and M. Cui, "Molecular docking: a powerful approach for structure-based drug discovery," Current computer-aided drug design, vol. 7, no. 2, pp. 146-157, 2011.
O. Trott and A. J. Olson, "AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading," Journal of computational chemistry, vol. 31, no. 2, pp. 455-461, 2010.
M. R. R. Rahardhian, Y. Susilawati, I. Musfiroh, R. M. Febriyanti, M. Muchtaridi, and S. A. Sumiwi, "In silico study of bioactive compounds from sungkai (Peronema canescens) as an immunomodulator," Int J Appl Pharm, vol. 14, no. 4, pp. 135-141, 2022.
M. I. Shalihin, A. Khatib, Y. Yusnaidar, I.L. Tarigan, and M. Latief, "An in-vogue plant, Peronema canescens Jack: traditional uses and scientific evidence of its bioactivities," Discover Plants, vol. 1, no. 1, p. 58, 2024.
M. Kanedi, K. Handayani, and W. A. Setiawan, "Therapeutic potentials of sungkai (Peronema canescens Jack) an Indonesian luxurious woody plant," World J Biol Pharm Heal Sci, vol. 11, no. 1, pp. 069-073, 2022.
T. C. Maigoda, J. Judiono, D. B. Purkon, and A. N. E. M. Haerussana, "Peronema canescens ethanol extract attenuates inflammatory biomarkers and lung damage in ARDS rats animal models induced by LPS," Journal of Applied Pharmaceutical Science, vol. 13, no. 12, pp. 123-131, 2023.
M. Priyadi, R. R. Saputra, Y. E. Gunawan, S. Citrariana, D. Decenly, and Y. Febrianto, "Aktivitas Psikostimulan Tanaman Bajakah (Spatholobus suberectus): Studi In Silico Terhadap Protein 4M48-Dopamine Transporter," Jurnal Farmasi & Sains Indonesia, vol. 6, no. 2, pp. 149-154, 2023.
Z.-j. Jia et al., "Synthesis, molecular docking, and binding Gibbs free energy calculation of β-nitrostyrene derivatives: Potential inhibitors of SARS-CoV-2 3CL protease," Journal of Molecular Structure, vol. 1284, p. 135409, 2023.
I.-F. Darie, S. Gosav, and M. Praisler, "Evaluation of physico-chemical parameters of some psychoactive compounds based on molecular modeling," Analele Universității” Dunărea de Jos” din Galați. Fascicula II, Matematică, fizică, mecanică teoretică/Annals of the” Dunarea de Jos” University of Galati. Fascicle II, Mathematics, Physics, Theoretical Mechanics, vol. 46, no. 1, pp. 1-4, 2023.
M. El Fadili et al., "QSAR, ADMET in silico pharmacokinetics, molecular docking and molecular dynamics studies of novel bicyclo (aryl methyl) benzamides as potent GlyT1 inhibitors for treating schizophrenia," Pharmaceuticals, vol. 15, no. 6, p. 670, 2022.
A. Penmatsa, K. H. Wang, and E. Gouaux, "X-ray structure of dopamine transporter elucidates antidepressant mechanism," Nature, vol. 503, no. 7474, pp. 85-90, 2013.
S. Forli, R. Huey, M. E. Pique, M. F. Sanner, D. S. Goodsell, and A. J. Olson, "Computational protein-ligand docking and virtual drug screening with the AutoDock suite," Nature protocols, vol. 11, no. 5, pp. 905-919, 2016.
M. d. S. P. Gonzalez, C. Cheohen, B. V. Andriolo, and M. L. da Silva, "Development of a Database of Peptides with Potential for Pharmacological Intervention in Human Pathogen Molecular Targets," Latin American Data in Science, vol. 3, no. 1, pp. 16-21, 2023.
J. Eberhardt, D. Santos-Martins, A. F. Tillack, and S. Forli, "AutoDock Vina 1.2. 0: New docking methods, expanded force field, and python bindings," Journal of chemical information and modeling, vol. 61, no. 8, pp. 3891-3898, 2021.
K. H. Wang, A. Penmatsa, and E. Gouaux, "Neurotransmitter and psychostimulant recognition by the dopamine transporter," Nature, vol. 521, no. 7552, pp. 322-327, 2015.
R. R. Saputra, S. M. Ulfa, and M. F. Rahman, "Novel bromoalkyl-1, 4- benzoquinones as anti-inflammatory candidate toward COX signaling: Synthesis, octanol-water solubility, and in- silico drug-target profiling," vol. 3055: AIP Publishing.
S. Sharma, A. Sharma, and U. Gupta, "Molecular Docking studies on the Anti-fungal activity of Allium sativum (Garlic) against Mucormycosis (black fungus) by BIOVIA discovery studio visualizer 21.1. 0.0," Annals of Antivirals and Antiretrovirals, vol. 5, no. 1, pp. 028-032, 2021.
Y. Chen, H. Zhang, W. Wang, Y. Shen, and Z. Ping, "Rapid generation of high-quality structure figures for publication with PyMOL-PUB," Bioinformatics, vol. 40, no. 3, p. btae139, 2024.
T. K. Karami, S. Hailu, S. Feng, R. Graham, and H. J. Gukasyan, "Eyes on Lipinski's rule of five: a new “rule of thumb” for physicochemical design space of ophthalmic drugs," Journal of ocular pharmacology and therapeutics, vol. 38, no. 1, pp. 43-55, 2022.
M. Gupta, R. Sharma, and A. Kumar, "Docking techniques in pharmacology: How promising?" Computational biology and chemistry, vol. 76, pp. 210- 217, 2018.
R. Jakhar, M. Dangi, A. Khichi, and A. K. Chhillar, "Relevance of molecular docking studies in drug designing," Current Bioinformatics, vol. 15, no. 4, pp. 270-278, 2020.
D. K. Srivastava et al., "Structure of the human dopamine transporter and mechanisms of inhibition," Nature, vol. 632, no. 8025, pp. 672-677, 2024.
H. Wang, A. Goehring, K. H. Wang, A. Penmatsa, R. Ressler, and E. Gouaux, "Structural basis for action by diverse antidepressants on biogenic amine transporters," Nature, vol. 503, no. 7474, pp. 141-145, 2013.
M. H. Cheng and I. Bahar, "Molecular mechanism of dopamine transport by human dopamine transporter," Structure, vol. 23, no. 11, pp. 2171-2181, 2015.
L. Zell, A. Bretl, V. Temml, and D. Schuster, "Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight," Biomedicines, vol. 11, no. 5, p. 1468, 2023.
P. D. Bosshart, R.-P. Charles, R.-A. A. Garibsingh, A. Schlessinger, and D. Fotiadis, "SLC16 family: from atomic structure to human disease," Trends in biochemical sciences, vol. 46, no. 1, pp. 28-40, 2021.
D. K. Tosh et al., "A3 adenosine receptor agonists containing dopamine moieties for enhanced interspecies affinity," European journal of medicinal chemistry, vol. 228, p. 113983, 2022.
A. G. Atanasov, S. B. Zotchev, V. M. Dirsch, and C. T. Supuran, "Natural products in drug discovery: advances and opportunities," Nature Reviews Drug Discovery, vol. 20, no. 3, pp. 200-216, 2021.
H. Feng et al., "Machine learning analysis of cocaine addiction informed by DAT, SERT, and NET-based interactome networks," Journal of Chemical Theory and Computation, vol. 18, no. 4, pp. 2703-2719, 2022.
K. R. Surana, E. D. Ahire, V. N. Sonawane, and S. G. Talele, "Biomolecular and molecular docking: A modern tool in drug discovery and virtual screening of natural products," in Applied Pharmaceutical Practice and Nutraceuticals: Apple Academic Press, 2021, pp. 209-223.
C. a Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney, "Experimental and computational approaches to estimate solubility and permeability in drug discovery and developmental settings," Adv Drug Deliv Rev, vol. 46, no. 1–3, pp. 3-26, 2001.
Z. Rankovic, "CNS physicochemical property space shaped by a diverse set of molecules with experimentally determined exposure in the mouse brain: mini perspective," Journal of Medicinal Chemistry, vol. 60, no. 14, pp. 5943-5954, 2017.
F. Svensson, U. Norinder, and A. Bender, "Improving screening efficiency through iterative screening using docking and conformal prediction," Journal of Chemical Information and Modeling, vol. 57, no. 3, pp. 439-444, 2017.
A. V. Sadybekov and V. Katritch, "Computational approaches streamlining drug discovery," Nature, vol. 616, no. 7958, pp. 673-685, 2023.
L. G. Knowles, A. J. Armanious, Y. Peng, W. J. Welsh, and M. H. James, "Recent advances in drug discovery efforts targeting the sigma one receptor system: Implications for novel medications designed to reduce excessive drug and food seeking," Addiction neuroscience, vol. 8,p. 100126, 2023.
Unduhan
Diterbitkan
Cara Mengutip
Terbitan
Bagian
Lisensi
Hak Cipta (c) 2025 Helium: Journal of Science and Applied Chemistry
Artikel ini berlisensiCreative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
