Molecular docking analysis and dynamics simulation of ethanol extract of Citrus sinensis as a Keap1 and NMDA inhibitor in brain injury

Syaban,Mokhamad Fahmi Rizki; Putra,Gumilar Fardhani Ami; Vadhana,Rossa Arianda; Muhyiddin,Afrizal Alif Azzam; Farida,Lia Dia; Sabila,Faradilah Lukmana; Haitsam,Muhammad; Santoso,Widodo Mardi

doi:10.3892/wasj.2023.191

Molecular docking analysis and dynamics simulation of ethanol extract of Citrus sinensis as a Keap1 and NMDA inhibitor in brain injury

Authors:
- Mokhamad Fahmi Rizki Syaban
- Gumilar Fardhani Ami Putra
- Rossa Arianda Vadhana
- Afrizal Alif Azzam Muhyiddin
- Lia Dia Farida
- Faradilah Lukmana Sabila
- Muhammad Haitsam
- Widodo Mardi Santoso
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Affiliations: Faculty of Medicine, Brawijaya University, Malang 65145, Indonesia, Master Program in Biomedical Science, Faculty of Medicine, Brawijaya University, Malang 65145, Indonesia, Department of Neurology, Faculty of Medicine, Saiful Anwar General Hospital, Brawijaya University, Malang 65145, Indonesia
Published online on: February 23, 2023 https://doi.org/10.3892/wasj.2023.191
Article Number: 14
Copyright: © Syaban et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Traumatic brain injury is a significant cause of mortality in young adults and disability in all age groups. This is followed by secondary injury involving various processes, such as oxidative stress which induce neuronal apoptosis. The present study aimed to analyze the active compounds of Citrus sinensis and predict its antioxidative activity in traumatic brain injury. Liquid chromatography/high resolution mass spectrometry (LC/HRMS) was used to identify compounds in the ethanol extract of Citrus sinensis peel. We analyzed pharmacokinetics, blood‑brain barrier (BBB) permeability and the toxicity of active compounds in Citrus sinensis peel using SwissADME and OSIRIS. The compounds with a good BBB permeability were subjected to molecular docking analysis to identify the molecular interaction with Kelch‑like ECH associated protein 1 (Keap1) and N‑methyl‑D‑aspartate (NMDA) proteins using PyRx, PyMol and Discovery Studio software. The results of the LC/HRMS analysis revealed 16 active compounds contained in the ethanol extract of the orange peel. Nootkatone, alminoprofen, linoleic acid, chanoclavine, scoparone and tangeretin were predicted to pass the BBB. The active compounds of Citrus sinensis strongly bound against Keap1 and NMDA, particularly scoparone and nootkatone. The strong binding affinity of scoparone‑Keap1 was ‑5.0, more than that of the control ligand, and that of nootkatone‑NMDA was ‑7.8, similar to the control ligand. The active compounds of Citrus sinensis peel exhibited inhibitory potential, good pharmacokinetics and toxicity profiles against Keap1 and NMDA. On the whole, these findings suggest that ethanol extract of Citrus sinensis peel has potential for use as an oxidative stress inhibitor in the treatment of brain injury.

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1	Maas AIR, Menon DK, Adelson PD, Andelic N, Bell MJ, Belli A, Bragge P, Brazinova A, Büki A, Chesnut RM, et al: Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 16:987–1048. 2017.PubMed/NCBI View Article : Google Scholar
2	Xiong C, Hanafy S, Chan V, Hu ZJ, Sutton M, Escobar M, Colantonio A and Mollayeva T: Comorbidity in adults with traumatic brain injury and all-cause mortality: A systematic review. BMJ Open. 9(e029072)2019.PubMed/NCBI View Article : Google Scholar
3	Dorsett CR, McGuire JL, DePasquale EAK, Gardner AE, Floyd CL and McCullumsmith RE: Glutamate neurotransmission in rodent models of traumatic brain injury. J Neurotrauma. 34:263–272. 2017.PubMed/NCBI View Article : Google Scholar
4	Thapa K, Khan H, Singh TG and Kaur A: Traumatic brain injury: Mechanistic insight on pathophysiology and potential therapeutic targets. J Mol Neurosci. 71:1725–1742. 2021.PubMed/NCBI View Article : Google Scholar
5	Khatri N, Thakur M, Pareek V, Kumar S, Sharma S and Datusalia AK: Oxidative stress: Major threat in traumatic brain injury. CNS Neurol Disord Drug Targets. 17:689–695. 2018.PubMed/NCBI View Article : Google Scholar
6	Kurniawan DB, Syaban MFR, Mufidah A, Zulfikri MUR and Riawan W: Protective effect of Saccharomyces cerevisiae in Rattus norvegicus Ischemic Stroke Model. Res J Pharm Technol. 14:5785–5789. 2021.
7	Kansanen E, Kuosmanen SM, Leinonen H and Levonen AL: The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biol. 1:45–49. 2013.PubMed/NCBI View Article : Google Scholar
8	Baird L and Yamamoto M: The molecular mechanisms regulating the KEAP1-NRF2 pathway. Mol Cell Biol. 40:e00099–20. 2020.PubMed/NCBI View Article : Google Scholar
9	Bhowmick S, D'Mello V, Caruso D and Abdul-Muneer PM: Traumatic brain injury-induced downregulation of Nrf2 activates inflammatory response and apoptotic cell death. J Mol Med (Berl). 97:1627–1641. 2019.PubMed/NCBI View Article : Google Scholar
10	Liang J, Wu S, Xie W and He H: Ketamine ameliorates oxidative stress-induced apoptosis in experimental traumatic brain injury via the Nrf2 pathway. Drug Des Devel Ther. 12:845–853. 2018.PubMed/NCBI View Article : Google Scholar
11	Rafiq S, Kaul R, Sofi SA, Bashir N, Nazir F and Ahmad Nayik G: Citrus peel as a source of functional ingredient: A review. J Saudi Soc Agric Sci. 17:351–358. 2018.
12	Saini RK, Ranjit A, Sharma K, Prasad P, Shang X, Gowda KGM and Keum YS: Bioactive compounds of citrus fruits: A review of composition and health benefits of carotenoids, flavonoids, limonoids, and terpenes. Antioxidants (Basel). 11(239)2022.PubMed/NCBI View Article : Google Scholar
13	Singh B, Singh JP, Kaur A and Singh N: Phenolic composition, antioxidant potential and health benefits of citrus peel. Food Res Int. 132(109114)2020.PubMed/NCBI View Article : Google Scholar
14	Abdelghffar EA, El-Nashar HAS, AL-Mohammadi AGA and Eldahshan OA: Orange fruit (Citrus sinensis) peel extract attenuates chemotherapy-induced toxicity in male rats. Food Funct. 12:9443–9455. 2021.PubMed/NCBI View Article : Google Scholar
15	Li X, Xie P, Hou Y, Chen S, He P, Xiao Z, Zhan J, Luo D, Gu M and Lin D: Tangeretin inhibits oxidative stress and inflammation via upregulating Nrf-2 signaling pathway in collagen-induced arthritic rats. Pharmacology. 104:187–195. 2019.PubMed/NCBI View Article : Google Scholar
16	Sahu DR, Chowdhury B and Sahoo BM: Anti-convulsant action and attenuation of oxidative stress by citrus limon peel extracts in PTZ and MES induced convulsion in albino rats. Cent Nerv Syst Agents Med Chem. 20:177–185. 2020.PubMed/NCBI View Article : Google Scholar
17	Pinzi L and Rastelli G: Molecular Docking: Shifting paradigms in drug discovery. Int J Mol Sci. 20(4331)2019.PubMed/NCBI View Article : Google Scholar
18	Sander T, Freyss J, von Korff M, Reich JR and Rufener C: OSIRIS, an entirely in-house developed drug discovery informatics system. J Chem Inf Model. 49:232–246. 2009.PubMed/NCBI View Article : Google Scholar
19	Rahman PA, Syaban MFR, Anoraga SG and Sabila FL: Molecular docking analysis from Bryophyllum pinnatum Compound as A COVID-19 cytokine storm therapy. Open Access Maced J Med Sci. 10:779–784. 2022.
20	Zhong M, Lynch A, Muellers SN, Jehle S, Luo L, Hall DR, Iwase R, Carolan JP, Egbert M, Wakefield A, et al: Interaction energetics and druggability of the protein-protein interaction between Kelch-like ECH-Associated Protein 1 (KEAP1) and nuclear factor erythroid 2 like 2 (Nrf2). Biochemistry. 59:563–581. 2020.PubMed/NCBI View Article : Google Scholar
21	Lipinski CA: Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov Today Technol. 1:337–341. 2004.PubMed/NCBI View Article : Google Scholar
22	Daina A and Zoete V: A BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem. 11:1117–1121. 2016.PubMed/NCBI View Article : Google Scholar
23	Kharisma VD, Widyananda MH, Ansori ANM, Nege AS, Naw SW and Nugraha AP: Tea catechin as antiviral agent via apoptosis agonist and triple inhibitor mechanism against HIV-1 infection: A bioinformatics approach. J Pharm Pharmacogn Res. 9:435–445. 2021.
24	Yueniwati Y, Rizki Syaban MF, Faratisha IFD, Yunita KC, Kurniawan DB, Putra GFA and Erwan NE: Molecular docking approach of natural compound from herbal medicine in java against severe acute respiratory syndrome coronavirus-2 receptor. Open Access Maced J Med Sci. 9:1181–1186. 2021.PubMed/NCBI View Article : Google Scholar
25	Nugraha RY, Faratisha IF, Mardhiyyah K, Ariel DG, Putri FF, Nafisatuzzamrudah Winarsih S, Sardjono TW and Fitri LE: Antimalarial properties of isoquinoline derivative from streptomyces hygroscopicus subsp. Hygroscopicus: An in silico approach. BioMed Res Int. 2020(6135696)2020.PubMed/NCBI View Article : Google Scholar
26	Yueniwati Y, Syaban MFR, Erwan NE, Putra GFA and Krisnayana AD: Molecular docking analysis of ficus religiosa active compound with anti-inflammatory activity by targeting tumour necrosis factor alpha and vascular endothelial growth factor receptor in diabetic wound healing. Open Access Maced J Med Sci. 9:1031–1036. 2021.
27	Yuniwati Y, Syaban MFR, Anoraga SG and Sabila FL: Molecular docking approach of bryophyllum pinnatum compounds as atherosclerosis therapy by targeting adenosine monophosphate-activated protein kinase and inducible nitric oxide synthase. Acta Inform Med. 30:91–95. 2022.PubMed/NCBI View Article : Google Scholar
28	Yao W, Lin S, Su J, Cao Q, Chen Y, Chen J, Zhang Z, Hashimoto K, Qi Q and Zhang JC: Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents. Transl Psychiatry. 11(140)2021.PubMed/NCBI View Article : Google Scholar
29	Vishvakarma VK, Singh MB, Jain P, Kumari K and Singh P: Hunting the main protease of SARS-CoV-2 by plitidepsin: Molecular docking and temperature-dependent molecular dynamics simulations. Amino Acids. 54:205–213. 2022.PubMed/NCBI View Article : Google Scholar
30	Wu C, Li T, Zhu B, Zhu R, Zhang Y, Xing F and Chen Y: Scoparone protects neuronal cells from oxygen glucose deprivation/reoxygenation injury. RSC Adv. 9:2302–2308. 2019.PubMed/NCBI View Article : Google Scholar
31	Lyu L, Chen J, Wang W, Yan T, Lin J, Gao H, Li H, Lv R, Xu F, Fang L and Chen Y: Scoparone alleviates Ang II-induced pathological myocardial hypertrophy in mice by inhibiting oxidative stress. J Cell Mol Med. 25:3136–3148. 2021.PubMed/NCBI View Article : Google Scholar
32	Shohami E and Biegon A: Novel approach to the role of NMDA receptors in traumatic brain injury. CNS Neurol Disord Drug Targets. 13:567–573. 2014.PubMed/NCBI View Article : Google Scholar
33	Ugale VG and Bari SB: Structural exploration of quinazolin-4(3H)-ones as Anticonvulsants: Rational design, synthesis, pharmacological evaluation, and molecular docking studies. Arch Pharm (Weinheim). 349:864–880. 2016.PubMed/NCBI View Article : Google Scholar
34	Martínez L: Automatic identification of mobile and rigid substructures in molecular dynamics simulations and fractional structural fluctuation analysis. PLoS One. 10(e0119264)2015.PubMed/NCBI View Article : Google Scholar
35	Luo P, Li X, Wu X, Dai S, Yang Y, Xu H, Jing D, Rao W, Xu H, Gao X, et al: Preso regulates NMDA receptor-mediated excitotoxicity via modulating nitric oxide and calcium responses after traumatic brain injury. Cell Death Dis. 10(496)2019.PubMed/NCBI View Article : Google Scholar
36	Carvajal FJ, Mattison HA and Cerpa W: Role of NMDA receptor-mediated glutamatergic signaling in chronic and acute neuropathologies. Neural Plast. 2016(2701526)2016.PubMed/NCBI View Article : Google Scholar
37	Yan T, Li F, Xiong W, Wu B, Xiao F, He B and Jia Y: Nootkatone improves anxiety- and depression-like behavior by targeting hyperammonemia-induced oxidative stress in D-galactosamine model of liver injury. Environ Toxicol. 36:694–706. 2021.PubMed/NCBI View Article : Google Scholar
38	Park JE, Park JS, Leem YH, Kim DY and Kim HS: NQO1 mediates the anti-inflammatory effects of nootkatone in lipopolysaccharide-induced neuroinflammation by modulating the AMPK signaling pathway. Free Radic Biol Med. 164:354–368. 2021.PubMed/NCBI View Article : Google Scholar
39	Chen CM, Lin CY, Chung YP, Liu CH, Huang KT, Guan SS, Wu CT and Liu SH: Protective effects of nootkatone on renal inflammation, apoptosis, and fibrosis in a unilateral ureteral obstructive mouse model. Nutrients. 13(3921)2021.PubMed/NCBI View Article : Google Scholar
40	Akamatsu Y and Hanafy KA: Cell death and recovery in traumatic brain injury. Neurotherapeutics. 17:446–456. 2020.PubMed/NCBI View Article : Google Scholar
41	Kaya SS, Mahmood A, Li Y, Yavuz E, Göksel M and Chopp M: Apoptosis and expression of p53 response proteins and cyclin D1 after cortical impact in rat brain. Brain Res. 818:23–33. 1999.PubMed/NCBI View Article : Google Scholar
42	Clark RS, Chen J, Watkins SC, Kochanek PM, Chen M, Stetler RA, Loeffert JE and Graham SH: Apoptosis-suppressor gene bcl-2 expression after traumatic brain injury in rats. J Neurosci. 17:9172–9182. 1997.PubMed/NCBI View Article : Google Scholar
43	Conti AC, Raghupathi R, Trojanowski JQ and McIntosh TK: Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period. J Neurosci. 18:5663–5672. 1998.PubMed/NCBI View Article : Google Scholar
44	Sugawara T, Lewén A, Gasche Y, Yu F and Chan PH: Overexpression of SOD1 protects vulnerable motor neurons after spinal cord injury by attenuating mitochondrial cytochrome c release. FASEB J. 16:1997–1999. 2002.PubMed/NCBI View Article : Google Scholar
45	Kirkland RA, Windelborn JA, Kasprzak JM and Franklin JL: A Bax-induced pro-oxidant state is critical for cytochrome c release during programmed neuronal death. J Neurosci. 22:6480–6490. 2002.PubMed/NCBI View Article : Google Scholar