TY - JOUR T1 - Molecular modelling approaches for the identification of potent sodium-glucose cotransporter 2 inhibitors from Boerhavia diffusa for the potential treatment of chronic kidney disease AU - Sundar, Krishnan AU - Kabilan, Shanmugampillai Jeyarajaguru AU - Sivakumar, Oviya AU - Kunjiappan, Selvaraj AU - Pavadai, Parasuraman PY - 2025 DA - September Y2 - 2024 DO - 10.12991/jrespharm.1763488 JF - Journal of Research in Pharmacy JO - J. Res. Pharm. PB - Marmara University WT - DergiPark SN - 2630-6344 SP - 1851 EP - 1877 VL - 29 IS - 5 LA - en AB - Chronic Kidney Disease (CKD) is a major global health issue affecting 10–14% of the global population.The current study used molecular modelling tools to identify potential bioactive compounds from the folk medicinalplant, Boerhavia diffusa for the treatment of CKD. The target protein was identified as sodium/glucose co-transporter 2(SGLT2), which has been linked to the development of CKD. Using IMPPAT database, twenty-five bioactive moleculesfrom B. diffusa were identified and docked against the SGLT2 protein to determine their binding affinity. The moleculardocking of the twenty-five compounds B. diffusa revealed that punarnavoside (-10.2 kcal × mol-1), and flavone (-9.3 kcal ×mol-1) were potential drug candidates. Metabolites of punarnavoside were also predicted and re-docked with the sametarget. Among the metabolites, punarnavoside-1 exhibited a better docking score (-10.3 kcal × mol-1). Thepharmacokinetic and physico-chemical properties of the compounds were also predicted and assessed using web-basedtools. Punarnavoside and flavone exhibited drug-like properties while having a lower toxicity profile. According to thisstudy, the in-silico results of B. diffusa biomolecules were comparable to dapaglifozin, a standard CKD drug. As a result,punarnavoside and flavone are potent and safe SGLT2 inhibitors that could potentially be used in the treatment of CKD.Further experimental and clinical research is required to determine their efficacy and safety in the treatment of CKD. KW - Chronic kidney disease KW - Boerhavia diffusa KW - sodium/glucose co-transporter 2 KW - molecular modelling tools KW - SDG 3 CR - Levey AS, Coresh J. Chronic kidney disease. Lancet. 2012;379(9811):165-180. https://doi.org/10.1016/S0140- 6736(11)60178-5. CR - Levey AS, Atkins R, Coresh J, Cohen EP, Collins AJ, Eckardt KU, Nahas ME, Jaber BL, Jadoul M, Levin A, Powe NR, Rossert J, Wheeler DC, Lameire N, Eknoyan G. Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes. Kidney Int. 2007;72(3):247-259. https://doi.org/10.1038/sj.ki.5002343. CR - Valente MA, Hillege HL, Navis G, Voors AA, Dunselman PH, van Veldhuisen DJ, Damman K. The Chronic Kidney Disease Epidemiology Collaboration equation outperforms the Modification of Diet in Renal Disease equation for estimating glomerular filtration rate in chronic systolic heart failure. Eur J Heart Fail. 2014 ;16(1):86-94. https://doi.org/10.1093/eurjhf/hft128. CR - Webster AC, Nagler EV, Morton RL, Masson P. Chronic Kidney Disease. Lancet. 2017;389(10075):1238-1252. https://doi.org/10.1016/S0140-6736(16)32064-5. CR - Xie Y, Bowe B, Mokdad AH, Xian H, Yan Y, Li T, Maddukuri G, Tsai CY, Floyd T, Al-Aly Z. Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016. Kidney Int. 2018;94(3):567-581. https://doi.org/10.1016/j.kint.2018.04.011. CR - Dodd R, Palagyi A, Guild L, Jha V, Jan S. The impact of out-of-pocket costs on treatment commencement and adherence in chronic kidney disease: a systematic review. Health Policy Plan. 2018;33(9):1047-1054. https://doi.org/10.1093/heapol/czy081. CR - Basile C, Brandenburg V, Ureña Torres PA. Natural Vitamin D in Chronic Kidney Disease. Vitamin D in Chronic Kidney Disease. 2016:465-491. https://doi.org/10.1007/978-3-319-32507-1_28. CR - Ogutmen B, Yildirim A, Sever MS, Bozfakioglu S, Ataman R, Erek E, Cetin O, Emel A. Health-related quality of life after kidney transplantation in comparison intermittent hemodialysis, peritoneal dialysis, and normal controls. Transplant Proc. 2006;38(2):419-21. https://doi.org/10.1016/j.transproceed.2006.01.016. CR - Romagnani P, Remuzzi G, Glassock R, Levin A, Jager KJ, Tonelli M, Massy Z, Wanner C, Anders HJ. Chronic kidney disease. Nat Rev Dis Primers. 2017;3:17088. https://doi.org/10.1038/nrdp.2017.88. CR - Jha V. Herbal medicines and chronic kidney disease. Nephrology (Carlton). 2010;15 Suppl 2:10-17. https://doi.org/10.1111/j.1440-1797.2010.01305.x. CR - Prasathkumar M, Anisha S, Dhrisya C, Becky R, Sadhasivam S. Therapeutic and pharmacological efficacy of selective Indian medicinal plants–a review. Phytomedicine Plus. 2021;1(2):100029. https://doi.org/10.1016/j.phyplu.2021.100029. CR - Mishra S, Aeri V, Gaur PK, Jachak SM. Phytochemical, therapeutic, and ethnopharmacological overview for a traditionally important herb: Boerhavia diffusa Linn. BioMed Res Int. 2014;2014(1):808302. https://doi.org/10.1155/2014/808302. CR - Khan MU, Basist P, Zahiruddin S, Ibrahim M, Parveen R, Krishnan A, Ahmad S. Nephroprotective potential of Boerhaavia diffusa and Tinospora cordifolia herbal combination against diclofenac induced nephrotoxicity. South Afr J Bot. 2022;151:238-247. https://doi.org/10.1016/j.sajb.2022.01.038. CR - Gaur PK, Rastogi S, Lata K. Correlation between phytocompounds and pharmacological activities of Boerhavia diffusa Linn with traditional-ethnopharmacological insights. Phytomedicine Plus. 2022;2(2):100260. https://doi.org/10.1016/j.phyplu.2022.100260. CR - Patil KS, Bhalsing SR. Ethnomedicinal uses, phytochemistry and pharmacological properties of the genus Boerhavia. J Ethnopharmacol. 2016;182:200-220. https://doi.org/10.1016/j.jep.2016.01.042. CR - Oburai NL, Rao VV, Bonath RBN. Comparative clinical evaluation of Boerhavia diffusa root extract with standard Enalapril treatment in Canine chronic renal failure. J Ayurveda and Integr Med. 2015;6(3):150. https://doi.org/10.4103/0975-9476.166390. CR - Pareta SK, Patra KC, Mazumder PM, Sasmal D. Aqueous extract of Boerhaavia diffusa root ameliorates ethylene glycol-induced hyperoxaluric oxidative stress and renal injury in rat kidney. Pharm Biol. 2011;49(12):1224-1233. https://doi.org/10.3109/13880209.2011.581671. CR - Neumiller JJ, White JR, Campbell RK. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs. 2010;70:377-385. https://doi.org/10.2165/11318680-000000000-00000. CR - Yaribeygi H, Butler AE, Atkin SL, Katsiki N, Sahebkar A. Sodium–glucose cotransporter 2 inhibitors and inflammation in chronic kidney disease: Possible molecular pathways. J Cell Physiol. 2019;234(1):223-230. https://doi.org/10.1002/jcp.26851. CR - Winiarska A, Knysak M, Nabrdalik K, Gumprecht J, Stompór T. Inflammation and oxidative stress in diabetic kidney disease: the targets for SGLT2 inhibitors and GLP-1 receptor agonists. Int J Mol Sci. 2021;22(19):10822. https://doi.org/10.3390/ijms221910822. CR - Malathi K, Ramaiah S. Bioinformatics approaches for new drug discovery: a review. Biotechnol Genet Eng Rev. 2018;34(2):243-260. https://doi.org/10.1080/02648725.2018.1502984. CR - Kalimuthu AK, Panneerselvam T, Pavadai P, Pandian SRK, Sundar K, Murugesan S, Ammunje DN, Kumar S, Arunachalam S, Kunjiappan S. Pharmacoinformatics-based investigation of bioactive compounds of Rasam (South Indian recipe) against human cancer. Sci Rep. 2021;11(1):21488. https://doi.org/10.1038/s41598-021-01008-9. CR - Askari H, Sanadgol N, Azarnezhad A, Tajbakhsh A, Rafiei H, Safarpour AR, Gheibihayat SM, Raeis-Abdollahi E, Savardashtaki A, Ghanbariasad A, Omidifar N. Kidney diseases and COVID-19 infection: causes and effect, supportive therapeutics and nutritional perspectives. Heliyon. 2021;7(1):e06008. https://doi.org/10.1016/j.heliyon.2021.e06008. CR - Sinan KI, Akpulat U, Aldahish AA, Celik Altunoglu Y, Baloğlu MC, Zheleva-Dimitrova D, Gevrenova R, Lobine D, Mahomoodally MF, Etienne OK, Zengin G, Mahmud S, Capasso R. LC-MS/HRMS Analysis, Anti-Cancer, Anti- Enzymatic and Anti-Oxidant Effects of Boerhavia diffusa Extracts: A Potential Raw Material for Functional Applications. Antioxidants (Basel). 2021;10(12):2003. https://doi.org/10.3390/antiox10122003. CR - Lin X, Li X, Lin X. A review on applications of computational methods in drug screening and design. Molecules. 2020;25(6):1375. https://doi.org/10.3390/molecules25061375. CR - Ahmed S, Islam N, Shahinozzaman M, Fakayode SO, Afrin N, Halim MA. Virtual screening, molecular dynamics, density functional theory and quantitative structure activity relationship studies to design peroxisome proliferator- activated receptor-γ agonists as anti-diabetic drugs. J Biomol Struct Dyn. 2021;39(2):728-742. https://doi.org/10.1080/07391102.2020.1714482. CR - Vora J, Patel S, Sinha S, Sharma S, Srivastava A, Chhabria M, Shrivastava N. Structure based virtual screening, 3D- QSAR, molecular dynamics and ADMET studies for selection of natural inhibitors against structural and non- structural targets of Chikungunya. J Biomol Struct Dyn. 2019 ;37(12):3150-3161. https://doi.org/10.1080/07391102.2018.1509732. CR - DeFronzo RA, Reeves WB, Awad AS. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nature Rev Nephrol. 2021;17(5):319-334. https://doi.org/10.1038/s41581-021-00393-8. CR - Śledź P, Caflisch A. Protein structure-based drug design: from docking to molecular dynamics. Curr Opin Struct Biol. 2018;48:93-102. https://doi.org/10.1016/j.sbi.2017.10.010. CR - Selby-Pham SN, Miller RB, Howell K, Dunshea F, Bennett LE. Physicochemical properties of dietary phytochemicals can predict their passive absorption in the human small intestine. Sci Rep. 2017;7(1):1931. https://doi.org/10.1038/s41598-017-01888-w. CR - Jia C-Y, Li J-Y, Hao G-F, Yang G-F. A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Discov Today. 2020;25(1):248-258. https://doi.org/10.1016/j.drudis.2019.10.014. CR - Chen X, Li H, Tian L, Li Q, Luo J, Zhang Y. Analysis of the physicochemical properties of acaricides based on Lipinski's rule of five. J Comput Biol. 2020;27(9):1397-1406. https://doi.org/10.1089/cmb.2019.0323. CR - Palanichamy C, Pavadai P, Panneerselvam T, Arunachalam S, Babkiewicz E, Ram Kumar Pandian S, Shanmugampillai Jeyarajaguru K, Nayak Ammunje D, Kannan S, Chandrasekaran J, Sundar K, Maszczyk P, Kunjiappan S. Aphrodisiac Performance of Bioactive Compounds from Mimosa pudica Linn.: In Silico Molecular Docking and Dynamics Simulation Approach. Molecules. 2022;27(12):3799. https://doi.org/10.3390/molecules27123799. CR - Tsopelas F, Tsagkrasouli M, Poursanidis P, Pitsaki M, Vasios G, Danias P, Panderi I, Tsantili-Kakoulidou A, Giaginis C. Retention behavior of flavonoids on immobilized artificial membrane chromatography and correlation with cell-based permeability. Biomed Chromatogr. 2018;32(3). https://doi.org/10.1002/bmc.4108. CR - Rathaur P, S R JK. Metabolism and Pharmacokinetics of Phytochemicals in the Human Body. Curr Drug Metab. 2019;20(14):1085-1102. https://doi.org/10.2174/1389200221666200103090757. CR - Ahmad I, Khan H, Serdaroğlu G. Physicochemical properties, drug likeness, ADMET, DFT studies, and in vitro antioxidant activity of oxindole derivatives. Comput Biol Chem. 2023;104:107861. https://doi.org/10.1016/j.compbiolchem.2023.107861. CR - Adekoya OC, Adekoya GJ, Sadiku ER, Hamam Y, Ray SS. Application of DFT calculations in designing polymer- based drug delivery systems: An overview. Pharmaceutics. 2022;14(9):1972. https://doi.org/10.3390/pharmaceutics14091972. CR - Akash S, Aovi FI, Azad MAK, Kumer A, Chakma U, Islam MR, Mukerjee N, Rahman MM, Bayıl I, Rashid S, Sharma R. A drug design strategy based on molecular docking and molecular dynamics simulations applied to development of inhibitor against triple-negative breast cancer by Scutellarein derivatives. Plos One. 2023;18(10):e0283271. https://doi.org/10.1371/journal.pone.0283271. CR - Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B, Zaslavsky L, Zhang J, Bolton EE. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021 ;49(D1):D1388-D1395. https://doi.org/10.1093/nar/gkaa971. CR - Mohanraj K, Karthikeyan BS, Vivek-Ananth RP, Chand RPB, Aparna SR, Mangalapandi P, Samal A. IMPPAT: A curated database of Indian Medicinal Plants, Phytochemistry And Therapeutics. Sci Rep. 2018;8(1):4329. https://doi.org/10.1038/s41598-018-22631-z. CR - Zhou Y, Zhang Y, Lian X, Li F, Wang C, Zhu F, Qiu Y, Chen Y. Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents. Nucleic Acids Res. 2022 Jan 7;50(D1):D1398- D1407. https://doi.org/10.1093/nar/gkab953. CR - Luebbert L, Pachter L. Efficient querying of genomic reference databases with gget. Bioinformatics. 2023;39(1):btac836. https://doi.org/10.1093/bioinformatics/btac836. CR - Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer TAP, Rempfer C, Bordoli L, Lepore R, Schwede T. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46(W1):W296-W303. https://doi.org/10.1093/nar/gky427. CR - Studer G, Rempfer C, Waterhouse AM, Gumienny R, Haas J, Schwede T. QMEANDisCo—distance constraints applied on model quality estimation. Bioinformatics. 2020;36(6):1765-1771. https://doi.org/10.1093/bioinformatics/btz828. CR - Jendele L, Krivak R, Skoda P, Novotny M, Hoksza D. PrankWeb: a web server for ligand binding site prediction and visualization. Nucleic Acids Res. 2019;47(W1):W345-W349. https://doi.org/10.1093/nar/gkz424. CR - Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods Mol Biol. 2015;1263:243- 250. https://doi.org/10.1007/978-1-4939-2269-7_19. CR - DeLano WL. Pymol: An open-source molecular graphics tool. CCP4 Newsl Protein Crystallogr. 2002;40(1):82-92. CR - Lohohola PO, Mbala BM, Bambi S-MN, Mawete DT, Matondo A, Mvondo JGM. In silico ADME/T properties of quinine derivatives using SwissADME and pkCSM webservers. Int J Trop Dis Health. 2021;42(11):1-12. https://doi.org/10.9734/ijtdh/2021/v42i1130492. CR - Jorgensen WL, Maxwell DS, Tirado-Rives J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc. 1996;118(45):11225-11236. https://doi.org/10.1021/ja9621760. CR - Martyna GJ, Klein ML, Tuckerman M. Nosé–Hoover chains: The canonical ensemble via continuous dynamics. J Chem Phys. 1992;97(4):2635-2643. https://doi.org/10.1063/1.463940. CR - Cheng A, Merz KM. Application of the Nosé− Hoover chain algorithm to the study of protein dynamics. J Phys Chem. 1996;100(5):1927-1937. https://doi.org/10.1021/jp951968y. CR - Kalibaeva G, Ferrario M, Ciccotti G. Constant pressure-constant temperature molecular dynamics: A correct constrained NPT ensemble using the molecular virial. Mol Phys. 2003;101(6):765-778. https://doi.org/10.1080/0026897021000044025. CR - Sánchez-Bojorge NA, Rodríguez-Valdez LM, Flores-Holguín N. DFT calculation of the electronic properties of fluorene-1, 3, 4-thiadiazole oligomers. J Mol Model. 2013;19:3537-3542. https://doi.org/10.3390/molecules27123799. CR - Parasuraman P, Alagarsamy V, Udayakumar P, Soundararajan M, Joshi SD, Ramalingam S, Ammunje DN. Graph theoretical analysis, in silico modeling, prediction of toxicity, metabolism and synthesis of novel 2- (methyl/phenyl)-3-(4-(5-substituted-1,3,4-oxadiazol-2-yl) phenyl) quinazolin-4(3H)-ones as NMDA receptor inhibitor. Drug Dev Res. 2019;80(3):368-385. https://doi.org/10.1002/ddr.21511. CR - Rydberg P, Gloriam DE, Olsen L. The SMARTCyp cytochrome P450 metabolism prediction server. Bioinformatics. 2010;26(23):2988-2989. https://doi.org/10.1093/bioinformatics/btq584. UR - https://doi.org/10.12991/jrespharm.1763488 L1 - https://dergipark.org.tr/en/download/article-file/5147401 ER -