In Silico Study of Bioactive Compounds from Red Fruit (Pandanus conoideus Lamk.) as Inhibitors of Human Alcohol Dehydrogenase
Article Sidebar
Views | PDF/EPUB Downloads:
0
/ 0
/ 0
Main Article Content
Abstract
Alcohol addiction and intoxication are serious global health issues, primarily influenced by the metabolic conversion of ethanol into acetaldehyde. This toxic substance causes various harmful effects on the liver, including alcoholic fatty liver (steatosis), steatohepatitis, fibrosis, and hepatocellular carcinoma. Meanwhile, alcohol dehydrogenase (ADH) enzyme facilitates the initial metabolic process. Inhibiting ADH is a potential therapeutic method to slow alcohol metabolism and reduce the side effects of acetaldehyde. Fomepizole is an efficient ADH inhibitor, and the use is limited due to several side effects and high costs, signifying the need to explore safer alternatives. Therefore, this study aimed to investigate the efficacy of bioactive compounds from Pandanus conoideus Lamk. (red fruit), an endemic plant from Papua, Indonesia, as potential ADH inhibitors using in silico methods. Molecular docking simulations and molecular dynamics were used to evaluate the compounds and identify the most promising candidates. Among the compounds evaluated through molecular docking, several flavonoids, such as 3,4',5-trihydroxy-7,3'-dimethoxy flavone (TDF) and taxifolin (TX), had the highest binding affinity scores towards ADH at -7.3 kcal/mol. The next compound producing the highest binding affinity score was quercetin (QE), with a value of -7.1 kcal/mol. Molecular dynamics simulations lasting more than 50 ns signified that QE was the most stable ligand, with root-mean-square deviation (RMSD) value that remained below 5 Å. The results generally showed that only QE from Pandanus conoideus had potential as ADH inhibitor.
Downloads
Article Details
Section
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
How to Cite
References
1.Rehm J, Shield KD. Global burden of alcohol use disorders and alcohol liver disease. Biomedicines. 2019; 7(4):7-6.
2.Bagnardi V, Blangiardo M, La Vecchia C, Corrao G. Alcohol consumption and the risk of cancer. Alcohol Res Health. 2001; 25(4):263 - 270.
3.Contreras-Zentella ML, Villalobos-García D, Hernández-Muñoz R. Ethanol metabolism in the liver, the induction of oxidant stress, and the antioxidant defense system. Antioxidants. 2022; 11(7):1-19.
4.Langhi C, Pedraz-Cuesta E, Haro D, Marrero PF, Rodríguez JC. Regulation of human class I alcohol dehydrogenases by bile acids. J. Lipid Res. 2013; 54(9):2475–2484.
5.Orywal K, Szmitkowski M. Alcohol dehydrogenase and aldehyde dehydrogenase in malignant neoplasms. Clin Exp Med. 2017; 17(2):131–139.
6.Ying X, Ma K. Characterization of a zinc-containing alcohol dehydrogenase with stereoselectivity from the hyperthermophilic archaeon Thermococcus guaymasensis. J Bacteriol. 2011; 193(12):3009–3019.
7.Hadi S, Setiawan D, Viogenta P, Sunardi S, Nastiti K, Nisa K, Andiarsa D. Molecular docking and dynamics study of compounds from Combretum indicumvar var. B seeds as alcohol dehydrogenase inhibitors. Trop J Nat Prod Res. 2023; 7(11):5087-5096.
8.Pereira AR, de Souza JCP, Gonçalves AD, Pagnoncelli KC, Crespilho FN. Bioelectrooxidation of ethanol using NAD-dependent alcohol dehydrogenase on oxidized flexible carbon fiber arrays. J. Braz Chem Soc. 2017; 00(00):1-10.
9.Martinez-Hurtado JL, Calo-Fernandez B, Vazquez-Padin J. Preventing and mitigating alcohol toxicity: a review on protective substances. Beverages (Basel). 2018; 4(39): 1 - 28.
10.Ashurst JV, Schaffer DH, Nappe TM. Methanol toxicity. In: StatPearls [internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2025 Aug 14]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK482121/
11.Mégarbane B. Treatment of patients with ethylene glycol or methanol poisoning: focus on fomepizole. Open Access Emerg Med. 2010; 2:67–75.
12.Battistella M. Fomepizole as an antidote for ethylene glycol poisoning. Ann Pharmacother. 2002; 36:1085–1089.
13.Nasim N, Sandeep IS, Mohanty S. Plant-derived natural products for drug discovery: current approaches and prospects. Nucleus (Calcutta). 2022; 65(3):399–411.
14.Lestari IT, Anggadiredja K, Garmana AN. Red fruit (Pandanus conoideus Lam) oil ameliorates streptozotocin-induced diabetic peripheral neuropathy by targeting the oxidative and inflammatory pathways in the spinal cord in a rat model. Pharmacia. 2024; 71:1–13.
15.Herdiyati Y, Atmaja HE, Satari MH, Kurnia D. Potential antibacterial flavonoid from red fruit (Pandanus conodieus Lam.) against pathogenic oral bacteria of Enterococcus faecalis ATCC 29212. Open Dent J. 2020; 14:433-439.
16.Astirin OP, Harini M, Handajani NS. The effect of crude extract of Pandanus conoideus Lam. var. yellow fruit on apoptosis expression of the breast cancer cells (T47D). Biodiversitas. 2009; 10(1):44-48.
17.Ainunnisa M, Fawwaz M, Pratama M. The antioxidant activity of red fruit juice (Pandanus conoideus Lam.) using the FRAP method. Pharm Rep. 2025; 4(1):5-10.
18.Damayanti L, Evaangelina IA, Laviana A, Herdiyati Y, Kurnia D. Antibacterial activity of buah merah (Pandanus conoideus Lam.) against bacterial oral pathogen of Streptococcus sanguinis ATCC10556, Streptococcus mutans ATCC 25175, and Enterococcus faecalis ATCC 29212: an in vitro study. Open Dent J. 2020; 14:113–119.
19.Umar AK. Flavonoid compounds of red fruit (Pandanus conoideus Lamk) as a potent SARS-CoV-2 main protease inhibitor: in silico approach. Future J Pharm Sci. 2021; 7(1):1-8.
20.Sirait MS, Warsiki E, Setyaningsih D. Potential of red fruit oil (Pandanus conoideus Lam.) as an antioxidant active packaging: a review. IOP Conf. Ser.: Earth Environ. Sci. 2021; 749:1-8.
21.Heriyanto, Gunawan IA, Fujii R, Maoka T, Shioi Y, Kameubun KMB, Limantara L, Brotosudarmo THP. Carotenoid composition in red fruit (Pandanus conoideus Lam.), an indigenous red fruit of the Papua islands. J Food Compos Anal. 2021; 96:3-31.
22.Lestari N, Junaidi L, Wijaya H, Wardayanie A, Ariningsih S. Development of processing technology for red fruit oil powder (Pandanus conoideus Lamk) as a food additive. Warta IHP. 2021; 38 (2):117-125.
23.Swanson K, Walther P, Leitz J, Mukherjee S, Wu JC, Shivnaraine RV, Zou J. ADMET-AI: a machine learning ADMET platform for evaluation of large-scale chemical libraries. Bioinformatics. 2024; 40(7):1-4.
24.Forli S, Huey R, Pique ME, Sanner MF, Goodsell DS, Olson AJ. Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat Protoc. 2016; 11(5):905–919.
25.Hurley TD, Bosron WF, Stone CL, Amzel LM. Structures of three human beta alcohol dehydrogenase variants - correlations with their functional differences. J Mol Biol. 1994; 239(3):415-429.
26.Shamsian S, Sokouti B, Dastmalchi S. Benchmarking different docking protocols for predicting the binding poses of ligands complexed with cyclooxygenase enzymes and screening chemical libraries. Bioimpacts. 2024; 14(2):1-9.
27.Rao P, Shukla A, Parmar P, Rawal RM, Patel B, Saraf M, Goswami D. Reckoning a fungal metabolite, Pyranonigrin A as a potential Main protease (Mpro) inhibitor of novel SARS-CoV-2 virus identified using docking and molecular dynamics simulation. Biophys Chem. 2020; 264:1-10.
28.Karami TK, Hailu S, Feng S, Graham R, Gukasyan HJ. Eyes on Lipinski's rule of five: a new "rule of thumb" for physicochemical design space of ophthalmic drugs. J Ocul Pharmacol Ther. 2022; 38(1):43–55.
29.Wu K, Kwon SH, Zhou X, Fuller C, Wang X, Vadgama J, Wu Y. Overcoming challenges in small-molecule drug bioavailability: a review of key factors and approaches. Int J Mol Sci. 2024; 25(23):1-29.
30.Guengerich FP. Cytochrome P450 and chemical toxicology. Chem Res Toxicol. 2008; 21(1):70–83.
31.Mukherjee S, Swanson K, Walther P, Shivnaraine RV, Leitz J, Pang PD, Zou J, Wu JC. ADMET-AI enables interpretable predictions of drug-induced cardiotoxicity. Circulation. 2025; 151(3):285–287.
32.Nogawa H, Kawai T. HERG trafficking inhibition in drug-induced lethal cardiac arrhythmia. Eur J Pharmacol. 2014; 741:336–339.
33.Didigwu OK, Nnadi CO. Theoretical drug-likeness, pharmacokinetic and toxicities of phytotoxic terpenoids from the toxic plants-phytotoxins. Trop J Nat Prod Res. 2024; 8(10):8867 –8873.
34.Vaidyanathan R, Sreedevi SM, Ravichandran K, Vinod SM, Krishnan YH, Babu LK, Parthiban PS, Basker L, Perumal T, Rajaraman V, Arumugam G, Rajendran K, Mahalingam V. Molecular docking approach on the binding stability of derivatives of phenolic acids (DPAs) with human serum albumin (HSA): Hydrogen-bonding versus hydrophobic interactions or combined influences?. JCIS Open. 2023; 12:1-16.
35.Spassov DS. Binding affinity determination in drug design: insights from lock and key, induced fit, conformational selection, and inhibitor trapping models. Int J Mol Sci. 2024; 25(13):1-20.
36.Amrulloh LSWF, Harmastuti N, Prasetiyo A, Herowati R. Analysis of molecular docking and dynamics simulation of mahogany (Swietenia macrophylla King) compounds against the PLpro Enzyme SARS-COV-2. J. farm. ilmu kefarmasian Indones. 2023; 10(3):347–359.
37.Fatriansyah JF, Rizqillah RK, Yandi MY, Fadilah, Sahlan M. Molecular docking and dynamics studies on propolis sulabiroin - A as a potential inhibitor of SARS-CoV-2. J. King Saud Univ Sci. 2022; 34(1):1-8.
38.Hayward S, Kitao A. Molecular dynamics simulations of NAD+-induced domain closure in horse liver alcohol dehydrogenase. Biophys J. 2006; 91(5):1823–1831.
39.Majumder R, Mandal M. Screening of plant-based natural compounds as a potential COVID-19 main protease inhibitor: an in silico docking and molecular dynamics simulation approach. J Biomol Struct Dyn. 2022; 40(2):696-711.
40.Rudnev VR, Nikolsky KS, Petrovsky DV, Kulikova LI, Kargatov AM, Malsagova KA, Stepanov AA, Kopylov AT, Kaysheva AL, Efimov AV. 3β-corner stability by comparative molecular dynamics simulations. Int J Mol Sci. 2022; 23(19):1-13.
41.Pace CN, Scholtz JM, Grimsley GR. Forces stabilizing proteins. FEBS Lett. 2014; 588(14):2177–2184.
42.Hanoush DA, Al-Auqaili AH, Mansour M, Ghosh A. Molecular docking, molecular dynamic simulation and ADME of some plant extracts and their effects on COVID-19 Patients. Trop J Nat Prod Res. 2022; 6(8):1233-1240.