Anti-diabetic activity of bioactive compounds extract from Ixora brachiata leaf: In-vitro and molecular docking, dynamics simulation approaches

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Doi: 10.1007/s42535-024-01139-0
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Keywords: n Ixora brachiatan , Molecular docking, Molecular dynamics simulation, ADMET


Abstract


This study focused on Ixora brachiata, a plant belonging to the Rubiaceae family, with the aim of analyzing its bioactive compounds and their interactions with the PPARγ enzyme. Using a combination of molecular docking, virtual screening, ADME/Toxicity assessments, and molecular dynamics simulations, the research investigated 17 compounds isolated from I. brachiata. Among them, compound 11 (Sulfurous acid, decyl 2-propyl ester) and compound 15 (Di-N-decylsulfone) showed significant binding interactions with key residues (Ser317, His351, His477, and Tyr501) in the enzyme’s active site. The ADME/T properties of both compounds were found to meet acceptable standards, including characteristics such as human intestinal absorption, blood-brain barrier permeability, topological polar surface area, and percentage of absorption. Additionally, both compounds adhered to the Lipinski rule of five, indicating their potential for good bioavailability. The binding free energy for compound 15 was calculated to be -46.08 kcal/mol over 150 nanoseconds, primarily driven by favorable van der Waals interactions (-50.45 kcal/mol). Decomposition analysis revealed that residues Ser317, Val367, Met392 and Tyr501 played essential roles in the ligand binding process. The study findings were consistent with the known bioactivity of I. brachiata and underscored the significant role of van der Waals forces in the molecular binding process. Molecular dynamics simulations, along with toxicity assessments, provided further insights into the safety and potential of these natural compounds for biomedical applications. Notably, compound 15 demonstrated strong potential as a promising candidate for further development in therapeutic applications.


n                     Ixora brachiatan                  , Molecular docking, Molecular dynamics simulation, ADMET


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References


Acharya CK, Das B, Madhu NR, Sau S, De M, Sarkar B (2023) A comprehensive pharmacological appraisal of Indian traditional medicinal plants with anti-diabetic potential. Advances in Diabetes Research and Management. Springer Nature Singapore, Singapore, pp 163–193


Achutha AS, Pushpa VL, Manoj KB (2021) Comparative molecular docking studies of phytochemicals as Jak2 inhibitors using Autodock and Argus Lab. Mater 41:711–716. https://doi.org/10.1016/j.matpr.2020.05.661


Agu PC, Afiukwa CA, Orji OU, Ezeh EM, Ofoke IH, Ogbu CO, Ugwuja EI, Aja PM (2023) Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Scientific Reports, 13(1), p.13398


Ali H, Houghton PJ, Soumyanath A (2006) α-Amylase inhibitory activity of some Malaysian plants used to treat diabetes; with particular reference to Phyllanthus amarus. J Ethnopharmacol 107(3):449–455. https://doi.org/10.1016/j.jep.2006.04.004


Atanasov AG, Zotchev SB, Dirsch VM, Supuran CT (2021) Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discovery 20(3):200–216


Bagaria A, Jaravine V, Huang YJ, Montelione GT, Güntert P (2012) Protein structure validation by generalized linear model root-mean-square deviation prediction. Protein Sci 21(2):229–238. https://doi.org/10.1002/pro.2007


Binu TV, Athira CB (2023) Evaluation of Medicinal Plant with Reference to Its Substitute. Bioprospecting of Tropical Medicinal Plants. Springer Nature Switzerland, Cham, pp 927–969


Bourais I, Elmarrkechy S, Taha D, Badaoui B, Mourabit Y, Salhi N, Alshahrani MM, Al Awadh AA, Bouyahya A, Goh KW, Tan CS (2022) Comparative Investigation of Chemical Constituents of Kernels, Leaves, Husk, and Bark of Juglans regia L., Using HPLC-DAD-ESI-MS/MS Analysis and Evaluation of Their Antioxidant, Antidiabetic, and Anti-Inflammatory Activities. Molecules 27(24):8989. https://doi.org/10.3390/molecules27248989


Case DA, Ben-Shalom IY, Brozell SR, Cerutti DS, Cheatham TE III, Cruzeiro VWD, Gohlke HAMBER (2018) University of California, San Francisco


Chakroun M, Khemakhem B, Mabrouk HB, El Abed H, Makni M, Bouaziz M, Drira N, Marrakchi N, Mejdoub H (2016) Evaluation of anti-diabetic and anti-tumoral activities of bioactive compounds from Phoenix dactylifera L’s leaf: In vitro and in vivo approach. Biomed Pharmacother 84:415–422. https://doi.org/10.1016/j.biopha.2016.09.062


Daoud NEH, Borah P, Deb PK, Venugopala KN, Hourani W, Alzweiri M, Bardaweel SK, Tiwari V (2021) ADMET profiling in drug discovery and development: perspectives of in silico, in vitro and integrated approaches. Curr Drug Metab 22(7):503–522. https://doi.org/10.2174/1389200222666210705122913


Dassault Systems BIOVIA (2016) Discovery Studio Modeling Environment, Release 2017. Dassault Systems, San Diego


Fagot-Campagna A, Pettitt DJ, Engelgau MM, Burrows NR, Geiss LS, Valdez R, Beckles GL, Saaddine J, Gregg EW, Williamson DF, Narayan KV (2000) Type 2 diabetes among North adolescents: An epidemiologic health perspective. J Pediatr 136(5):664–672. https://doi.org/10.1067/mpd.2000.105141


Gulçin İ, Taslimi P, Aygün A, Sadeghian N, Bastem E, Kufrevioglu OI, Turkan F, Şen F (2018) Antidiabetic and antiparasitic potentials: Inhibition effects of some natural antioxidant compounds on α-glycosidase, α-amylase and human glutathione S-transferase enzymes. Int J Biol Macromol 119:741–746


Haddou S, Elrherabi A, Loukili EH, Abdnim R, Hbika A, Bouhrim M, Kamaly A, Saleh O, Shahat A, Bnouham AA, M. and, Hammouti B (2023) Chemical Analysis of the Antihyperglycemic, and Pancreatic α-Amylase, Lipase, and Intestinal α-Glucosidase Inhibitory Activities of Cannabis sativa L. Seed Extracts. Molecules, 29(1), p.93


Hou T, Wan J, Li Y, Wang W (2011) Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J Chem Inf Model 51(1):69–82. https://doi.org/10.1021/ci100275a


Janani C, Kumari BR (2015) PPAR gamma gene–a review. Diabetes Metabolic Syndrome: Clin Res Reviews 9(1):46–50. https://doi.org/10.1016/j.dsx.2014.09.015


Jia CY, Li JY, Hao GF, Yang GF (2020) A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Discov Today 25(1):248–258. https://doi.org/10.1016/j.drudis.2019.10.014


Jones A, Leimkuhler B (2011) Adaptive stochastic methods for sampling driven molecular systems. Chem Phys 135(8):084125. https://doi.org/10.1063/1.3626941


Kazempour-Dizaji M, Mojtabavi S, Sadri A, Ghanbarpour A, Faramarzi MA, Navidpour L (2023) Arylureidoaurones: Synthesis, in vitro α-glucosidase, and α-amylase inhibition activity. Bioorg Chem 139:106709


Khalid M, Alqarni MH, Alsayari A, Foudah AI, Aljarba TM, Mukim M, Alamri MA, Abullais SS, Wahab S (2022) Anti-diabetic activity of bioactive compound extracted from spondias mangifera fruit: In-vitro and molecular docking approaches. Plants 11(4):562


Kifle ZD, Abdelwuhab M, Melak AD, Meseret T, Adugna M (2022) Pharmacological evaluation of medicinal plants with antidiabetic activities in Ethiopia: A review. Metabolism open 13:100174. https://doi.org/10.1016/j.metop.2022.100174


Kumar MS, Kaviya S, Parkavi G, Pavithra R, Thenmozhi R (2023) Molecular docking and antidiabetic activity of ethanol leaves extract of Spinacia oleracea. J Pharmacogn Phytochem 12(5):119–122. https://doi.org/10.22271/phyto.2023.v12.i5b.14714


Kumar S, Ayyannam SR (2023) Identification of new small molecule monoamine oxidase-B inhibitors through pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation studies. J Biomol Struct Dynamics 41(14):6789–6810


Kuwabara N, Oyama T, Tomioka D, Ohashi M, Yanagisawa J, Shimizu T, Miyachi H (2012) Peroxisome proliferator-activated receptors (PPARs) have multiple binding points that accommodate ligands in various conformations: phenylpropanoic acid-type PPAR ligands bind to PPAR in different conformations, depending on the subtype. J Med Chem 55(2):893–902. https://doi.org/10.1021/jm2014293


Loza-Rodríguez H, Estrada-Soto S, Alarcón-Aguilar FJ, Huang F, Aquino-Jarquín G, Fortis-Barrera Á, Giacoman-Martínez A, Almanza-Pérez JC (2020) Oleanolic acid induces a dual agonist action on PPARγ/α and GLUT4 translocation: A pentacyclictriterpene for dyslipidemia and type 2 diabetes. Eur J Pharmaco 883:173252


Mahapatra SR, Dey J, Raj TK, Kumar V, Ghosh M, Verma KK, Kaur T, Kesawat MS, Misra N, Suar M (2022) The potential of plant-derived secondary metabolites as novel drug candidates against Klebsiella pneumoniae: molecular docking and simulation investigation. S Afr J Bot 149:789–797. https://doi.org/10.1016/j.sajb.2022.04.043


Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE, Simmerling C (2015) ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J Chem Theory Comput 11(8):3696–3713. https://doi.org/10.1021/acs.jctc.5b00255


Mark P, Nilsson L (2001) Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. J Phys Chem A 105(43):9954–9960. https://doi.org/10.1021/jp003020w


Martyna GJ, Hughes A, Tuckerman ME (1999) Molecular dynamics algorithms for path integrals at constant pressure. Chem Phys 110(7):3275–3290. https://doi.org/10.1063/1.478193


Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791. https://doi.org/10.1002/jcc.21256


Noor F, Rehman A, Ashfaq UA, Saleem MH, Okla MK, Al-Hashimi A, AbdElgawad H, Aslam S (2022) Integrating network pharmacology and molecular docking approaches to decipher the multi-target pharmacological mechanism of Abrus precatorius L. acting on diabetes. Pharmaceuticals 15(4):414. https://doi.org/10.3390/ph15040414


Poojari M, Padyana S, Rao BR (2009) Evaluation of antioxidant and antimicrobial properties of Ixorabra chiata Roxb. J Chem 6:625–628. https://doi.org/10.1155/2009/962753


Prakash P, Vijayasarathi D, Selvam K, Karthi S, Manivasagaperumal R (2021) Pharmacore maping based on docking, ADME/toxicity, virtual screening on 3, 5- dimethyl-1, 3, 4-hexanetriol and dodecanoic acid derivates for anticancer inhibitors. J Biomol Struct Dyn 39(12):4490–4500. https://doi.org/10.1080/07391102.2020.1778533


Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A (2019) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18(1):41–58


Rochel N et al (2019) Recurrent activating mutations of PPARγ associated with luminal bladder tumors. Nat Commun 10(1):1–12


Roe DR, Cheatham III, T E (2013) PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory comput 9(7):3084–3095. https://doi.org/10.1021/ct400341p


Sadeghi-Nejad B, Deokule SS (2009) Antidermatophytic activities of Ixora brachiate Roxb. Afr J Biochem Res 3(10):344–348


Sajal H, Patil SM, Raj R, Shbeer AM, Ageel M, Ramu R (2022) Computer-aided screening of phytoconstituents from Ocimum tenuiflorum against diabetes mellitus targeting DPP4 inhibition: A combination of molecular docking, molecular dynamics, and pharmacokinetics approaches. Molecules 27(16):5133. https://doi.org/10.3390/molecules27165133


Sivasakthi V, Selvam K, Prakash P, Shivakumar MS, SenthilNathan S (2022) Characterization of silver nanoparticles using Ixora brachiata Roxb. and its biological application. Curr Res Green Sustain 5:100257. https://doi.org/10.1016/j.crgsc.2021.100257


Tafesse TB, Hymete A, Mekonnen Y, Tadesse M (2017) Antidiabetic activity and phytochemical screening of extracts of the leaves of Ajuga remota Benth on alloxan- induced diabetic mice. BMC complement Altern Med 17(1):1–9. https://doi.org/10.1016/j.crgsc.2021.100257


Van LV, Pham EC, Nguyen CV, Duong NTN, Le Thi TV, Truong TN (2022) In vitro and in vivo antidiabetic activity, isolation of flavonoids, and in silico molecular docking of stem extract of Merremia tridentata (L). Biomed Pharmacother 146:112611. https://doi.org/10.1016/j.biopha.2021.112611


Variya BC, Bakrania AK, Patel SS (2020) Antidiabetic potential of gallic acid from Emblica officinalis: Improved glucose transporters and insulin sensitivity through PPAR- γ and Akt signaling. Phytomedicine 73:152906. https://doi.org/10.1016/j.phymed.2019.152906


Widyawati T, AdlinYusoff N, Asmawi MZ, Ahmad M (2015) Antihyperglycemic effect of methanol extract of Syzygium polyanthum (Wight.) leaf in streptozotocin-induced diabetic rats. Nutrients 7(9):7764–7780. https://doi.org/10.3390/nu7095365


Zhang Y, Zhang TJ, Tu S, Zhang ZH, Meng FH (2020) Identification of novel Src inhibitors: Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulations. Molecules 25(18):4094. https://doi.org/10.3390/molecules25184094


Zhao C, Yang C, Wai STC, Zhang Y, Portillo P, Paoli M, Wu P, San Cheang Y, Liu W, Carpéné B, C. and, Xiao J (2019) Regulation of glucose metabolism by bioactive phytochemicals for the management of type 2 diabetes mellitus. Crit Rev Food Sci Nutr 59(6):830–847

 


Acknowledgements


The authors recognize and thank the Department of Botany, ERK Arts and Science College, Erumiyampatti, Dharmapuri, 636 905, Tamil Nadu, India.


Author Information


Sivasakthi Vairakkannu
Department of Botany, ERK Arts and Science College, Erumiyampatti, Dharmapuri, India
sivasakthi5676@gmail.com