In Silico Analysis of Antioxidant Phytochemicals with Potential NADPH Oxidase Inhibitory Effect
Abstract
Objective: NADPH oxidase (NOX) is known to produce reactive oxygen species (ROS) at physiological concentrations. However, it can be over-activated with some disease conditions and produces excess ROS. Several molecules have shown an ability to suppress the enzyme’s over-activity, although some weaknesses have been found. Hence, the attempt to screen phytochemicals, with the aim of finding the most specific and effective NOX inhibitor.
Material and Methods: The study was carried-out via an in-silico approach. First, phytochemicals with antioxidant activity, according to the literature review, were selected and downloaded from the PubChem database in SDF files. NOX with PDB: 2CDU was downloaded from the protein databank. Drug-likeness properties and biological activities were predicted using ADMETMESH and the Predict Activity Spectra of Substances (PASS) software. Phytochemical-NOX interactions were performed via molecular docking, whereas, docked conformations and bond residue amino acids were analyzed using Protein-plus software.
Results: The result of this study predicted 13 phytochemicals with drug-likeness properties, out of which 9 showed NOX-inhibitory activity. Docking results predicted all of the 9 phytochemicals were capable of interacting with NOX, by binding to at least one amino acid. The reference inhibitor (Apocynin, -8.3 kcal/mol) and some phytochemicals (caffeic, eriodictyol, hesperetin, and morin with ΔG -6.1 to -7.7 kcal/mol) were predicted to have bonded to Ser115, via hydrogen bonding. On the other hand, epicatechin gallate and quercetin with ΔG −8.7 and −8.1 kcal/mol did not bind to Ser115, but rather through other amino acids.
Conclusion: This study has led to the prediction of phytochemicals with NOX-inhibitory effects, which could be considered for further study.
Keywords
Full Text:
PDFReferences
Magnani F, Mattevi A. Structure and mechanisms of ROS generation by NADPH oxidases. Curr Opin Struct Biol 2019; 59:91–7.
Altenhofer S, Radermacher KA, Kleikers PWM, Wingler K, Schmidt HHHW. Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxid Redox Signal 2015;23:406-27.
Coso S, Harrison I, Harrison CB, Vinh A, Sobey CG, Drummond GR, et al. NADPH oxidases as regulators of tumor angiogenesis: current and emerging concepts. Antioxid Redox Signal 2012;16:1229–47.
Gaoand L, Mann GE. Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signaling. Cardiovascular Res 2009;82:9–20.
Bedard K and Krause KH. The NOX family of ROS generating NADPH oxidases: physiology and pathophysiology. Physiological Rev 2007;87:245–313.
Komatsu D, Kato M, Nakayama J, Miyagawa S, Kamata T. NADPH oxidase 1 plays a critical mediating role in oncogenic Ras-induced vascular endothelial growth factor expression. Oncogene 2008;27:4724–32.
Jiang F, Zhang Y, Dusting GJ. NADPH oxidase mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacological Rev 2011;63:218–42.
Sareila O, Kelkka T, Pizzolla A, Hultqvist M, Holmdahl R. NOX2 complex-derived ROS as immune regulators. Antioxid Redox Signal 2011;15:2197–208.
Kusaka I, Kusaka G, Zhou C, Ishikawa M, Nanda A, Granger DN, et al. Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. Am J Physiol Heart Circ Physiol 2004;286:H2442–51.
Santos AF, Povoa P, Paixao P, Mendonça A and Taborda- Barata L. Changes in Glycolytic Pathway in SARS-COV 2 Infection and Their Importance in Understanding the Severity of COVID-19. Front. Chem 2021;9:685196.
Baillet A, Hograindleur MA, El Benna J, Grichine A, Berthier S, Morel F, et al. Unexpected function of the phagocyte NADPH oxidase in supporting hyperglycolysis in stimulated Neutrophils: Key Role of 6phosphofructo-2-kinase. FASEB J 2017;31:663–73.
Delgado-Roche L, Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch Med Res 2020;51:384-7.
Das A, Durrant D, Koka S, Salloum FN, Xi L, Kukreja RC. Mammalian target of rapamycin (mTOR) inhibition with rapamycin improves cardiac function in type 2 diabetic mice: potential role of attenuated oxidative stress and altered contractile protein expression. J Biol Chem 2014;289:4145–60.
Davignon J, Jacob RF, Mason RP. The antioxidant effects of statins. Coron Artery Dis 200;15:51–8.
Esteghamati A, Eskandari D, Mirmiranpour H, Noshad S, Mousavizadeh M, Hedayati M, et al. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. Clin Nutr 2013;32:179-85.
Chen ZH, Qin WS, Zeng CH, Zheng CX, Hong YM, Lu YZ, et al. Triptolide reduces proteinuria in experimental membranous nephropathy and protects against C5b-9-induced podocyte injury in vitro. Kidney Int 2010;77:74–88.
Taye A, Morawietz H. Spironolactone inhibits NADPH oxidaseinduced oxidative stress and enhances eNOS in human endothelial cells. Iran J Pharm Res 2011;10:329–37.
Wang W, Wu QH, Sui Y, Wang Y, Qiu X. Rutin protects endothelial dysfunction by disturbing NOX4 and ROS-sensitive NLRP3 inflammasome. Biomed Pharmacother 2017;86:32–50.
Altenhofer S, Radermacher KA, Kleikers PWM, Wingler K, and Schmidt HHW. Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxid Redox Signal 2015;23:406-27.
Augsburger F, Filippova A, Rasti D, Seredenina T, Lam M, Maghzal G, et al. Pharmacological characterization of the seven human NOX isoforms and their inhibitors. Redox Biol 2019;26:101272.
Mazumdar S, Marar T, Devarajan S, Patki J. Functional relevance of Gedunin as a bona fide ligand of NADPH oxidase 5 and ROS scavenger: an in silico and in vitro assessment in a hyperglycemic RBC model. Biochem Biophys Rep 202;26: 100904.
Herrera-Calderon O, Chacaltana-Ramos LJ, Huayanca- Gutiérrez IC, Algarni MA, Alqarni M, Batiha GES. Chemical Constituents, In vitro antioxidant activity and in silico study on NADPH oxidase of Allium sativum L. (Garlic) essential oil. Antioxidants 2021;10:1-16.
Dos Santos WH, Yoguim MI, Dare RG, da Silva-Filho LC, Lautenschlager SOS Ximene VF. Development of a caffeic acid– phthalimide hybrid compound for NADPH oxidase inhibition. Royal Soc Chem 2021;11:17880-90.
Laksono AB, Kusumawati R, Suselo YH, Indarto D. In silico development of new candidate of NADPH oxidase inhibitor for hypertension treatment. Earth Environ Sci 2021;819:012071.
Ormachea C and Ferretti CA. In Silico evaluation of antioxidant properties of cinnamaldehyde phenylhydrazone. Chem Proc 2021;3:1-6.
Bedard K and Krause KH. The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology. Physiol Rev 2007;87:245–313.
Rahmani H, Ghavamipour F, Sajedi RH. Bioluminescence detection of superoxide anion using aequorin. Anal Chem 2019;91:12768–74.
da Silva Pantoja LVP, Trindade SSA, da Silva Carneiro A, Silva JPB, da Paixão TP, Romeiro CFR, et al. Computational study of the main flavonoids from Chrysobalanus icaco L. against NADPH-oxidase and in vitro Antioxidant Activity. Res Soc Development 2022;11:1-18.
Morris GM, Goodsell D S, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998;819:1639–62.
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multi-threading. J Comput Chem 2010;31: 455–61.
Laksono AB, Kusumawati R, Suselo YH, and Indarto D. In silico development of new candidate of NADPH oxidase inhibitor for hypertension treatment. Earth Environ Sci 2021:819.
da Costa JS, da Ramos RS, da Costa KS L, do Brasil DSB, de Paula da Silva CHT, Ferreira EFB, et al. An in silico study of the antioxidant ability for two caffeine analogs using molecular docking and quantum chemical methods. Molecules 2018;23:2801.
Zhang YJ, Gan RY, Li S, Zhou Y, Li AN, Xu DP, et al. Antioxidant phytochemicals for the prevention and treatment of chronic diseases. Molecules 2015;20:21138-56.
Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Techno 2004;1:337–41.
Xiong G, wu Z, Yi J, Fu L, Yang Z, Cao T, et al. ADMETlab 2.0: an intergrated online platform for accurate and comprehensive prediction of ADMET properties. Nucleic Acids Res 2021;49: W5-14.
Kritsi E, Tsiaka T, Ioannou AG, Mantanika V, Strati IF, Panderi I, et al. In vitro and in silico studies to assess edible flowers’ antioxidant activities. Appl Sci 2022;12:7331.
Ejembi SA, Johnson TO, Dabak JD, Akinsanmi AO, Oche JI, Francis T. Analysis of the oxidative stress inhibition potentials of Artemisia annua and its bioactive compounds through in vitro and in silico studies. J Pharm Bioresources 2021;18:245-59.
Farouk A, Mohsen M, Ali H, Shaaban H, Albaridi N. Antioxidant activity and molecular docking study of volatile constituents from different aromatic lamiaceous plants cultivated in Madinah Monawara, Saudi Arabia. Molecules 2021;26:41-5.
Mhya DH, Nuhu AA, Mankilik MM. In-silico discovery of antidiabetic drug potential of Balanites aegyptiaca leaf’s phenolic compounds. Natr Resour Human Health 2021;1:90-6.
Refbacks
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.