Anti-dengue Leads From Caesalpinia bonduc - An In Silico Approach
Abstract
Dengue (breakbone fever) is a rapidly spreading arboviral infection transmitted by Aedes mosquitoes with major public health implications in more than 100 tropical and subtropical countries mostly in Southeast Asia, South and Central America and the Western Pacific. As the virus spreads to new geographic areas, more frequent dengue outbreaks occur in different parts of the world. Fifty million cases of dengue occur worldwide each year, of which 10% require hospitalization for dengue hemorrhagic fever (DHF). It is a shocking truth that more than 90% of these are children under the age of five. The mortality rate is also significant as 2.5% die from dengue. Currently there is no effective vaccine or specific drug for Dengue/DHF. Pharmaceutical manufacturers have turned their attention to plant-based drug candidates to produce effective drugs. Following this the present study investigated the active phytochemicals present in the medicinal plant Caesalpinia bonduc (L.) Roxb. through docking simulation. Dengue virus non-structural protein five (NS5) and human IMPDH-II were used here as targets for docking with plant compounds. Docking results revealed that 33 compounds out of 82 phytochemicals showed better binding affinity than the native ligands of the targets. Compounds exhibiting the lowest free energy levels were further screened after studying their pharmacokinetics, medicinal chemistry friendliness, lead-likeness, and finally toxicity prediction to identify lead molecules. At the end of the study, three compounds, Caesaldekarin A, Caesalpinin F and Taepeenin D, which potently inhibited both targets, were selected here for further 'in vitro' and 'in vivo' studies.
Keywords:
Dengue, IMPDH, NS5-Mtase, Caesalpinia, phytochemical, Taepeenin, Caesaldekarin, diterpene, meroterpenoidDOI
https://doi.org/10.25004/IJPSDR.2023.150408References
Current ICTV taxonomy release. https://ictv.global/taxonomy browsed on 24th July, 2021.
Cogan JE: Dengue and severe dengue. WHO Fact sheets 2022; https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue
Plaisance KI, Mackowiak PA: Antipyretic therapy- Physiologic rationale, diagnostic implications, and clinical consequences. Arch intern Med. 2000; 160: 449-56.
Sheetal Verma and Singh SP: Current and future status of herbal medicines. Veterinary world, 2008; 1(11): 347-50.
Banupriya Ravichandran: Studies on Phytochemicals and anti-inflammatory activity of Caesalpinia bonducella Linn. J. Pharm. Res. 2018; 7(5): 63-69.
Gadakh MJ, Jadhav RS, Vikhe DN: Biological Potential of Caesalpinia bonducella Seed A Review; Journal of Drug Delivery and Therapeutics 2020; 10(3-s):308-10.
Kang S, Shields AR, Jupatanakul N, Dimopoulos G: Suppressing Dengue-2 Infection by Chemical Inhibition of Aedesaegypti Host Factors. PLoS Negl Trop Dis 2014; 8(8): 1-12.
BeritTroost, Smit JM: Recent advances in antiviral drug development towards dengue virus. Current Opinion in Virology 2020; 43:9–21.
Johnson MC, Kollman JM: Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation. ELife 2020; 9: 1-27.
Bairagyaa RH, Mukhopadhyaya BP, and Bera AK: Conserved water mediated recognition and the dynamics of active site Cys 331 and Tyr 411 in hydrated structure of human IMPDH-II. J. Mol. Recognit. 2011; 24: 35–44.
Hedstrom L: IMP Dehydrogenase: Structure, Mechanism and Inhibition. Chem Rev. 2009; 109(7): 2903–28.
Klema VJ, Ye M, Hindupur A, Teramoto T, Gottipati K, Padmanabhan R, et al.: Dengue Virus Nonstructural Protein 5 (NS5) Assembles into a Dimer with a Unique Methyltransferase and Polymerase Interface. PLoS Pathog 2016; 12(2): 1-21.
Moon K, Khadabadi SS, Deokate UA, Deore SL: Caessalpinia bonducella – an overview. Report and Opinion 2010; 2(3):83-90.
Manikandaselvi S, Vadivel V, Brindha P: Studies on Nutraceutical Properties of Caesalpinia bonducella L. An Indian Traditional Medicinal Plant. Res. J. Med. Plant 2016; 10: 127-39.
Sasidharan S, Srinivasa Kumar KP, Kanti Das S, Hareendran Nair J: Caesalpinia bonduc: A Ubiquitous yet Remarkable Tropical Plant Owing Various Promising Pharmacological and Medicinal Properties with Special References to the Seed. Med. Aromat. Plants (Los Angeles) 2021; 10: 394. 1-19.
Baldim Zanin JL, De Carvalho BA, Martineli PS: The genus Caesalpinia L. (Caesalpiniaceae): Phytochemical and pharmacological characteristics. Molecules 2012; 17: 7887-902.
Ata A, Gale ME, Samarasekera R: Bioactive chemical constituents of Caesalpinia bunduc (Fabaceae). Phytochemistry Letters 2009; 2: 106–109.
Kakade NR, Pingale SS, Chaskar MG: Phytochemical and pharmacological review of Caesalpinia bonducella. Int. J. Pharm 2016; 7(12): 12-17.
Mao F, Ni W, Xu X, Wang H, Wang J, Ji M, Li J: Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs. Molecules 2016; 21:1-18.
Cheng F, Yu Y, Zhou Y, Shen Z, Xiao W, Liu G, Li W, Lee PW, Tang Y: Insights into Molecular Basis of Cytochrome P450 Inhibitory Promiscuity of Compounds. J. Chem. Inf. Model. 2011; 51: 2482–95.
Gleeson MP: Generation of a Set of Simple, Interpretable ADMET Rules of Thumb. J. Med. Chem. 2008, 51: 817–34.
Md. Lutful Amin: P-glycoprotein Inhibition for Optimal Drug Delivery. Drug Target Insights 2013; 7: 27–34.
Veda P, Virapong P: P-Glycoprotein transporter in drug development. EXCLI Journal 2016; 15:113-18.
Finch A and Pillans P: P-glycoprotein and its role in drug-drug interactions. Australian prescriber 2014; 37(4): 137-39.
Carpenter TS, Kirshner DA, Lau EY, Wong SE, Nilmeier JP, and Lightstone FC: A Method to Predict Blood-Brain Barrier Permeability of Drug-Like Compounds Using Molecular Dynamics Simulations. Biophysical Journal 2014; 107: 630–41.
Guo-Hong Li, Zhi-JieNing, Yi-Ming Liu and Xiao-Hong Li: Neurological Manifestations of Dengue Infection. Frontiers in cellular and infection microbiology 2017; 7: 1-13.
Yan A, Wang Z, Cai Z: Prediction of Human Intestinal Absorption by GA Feature Selection and Support Vector Machine Regression. Int. J. Mol. Sci. 2008; 9: 1961-76.
McCarren P, Springer C, Whitehead L: An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential. Journal of Cheminformatics 2011; 3(51): 1-20.
Danker T, Moller C: Early identification of hERG liability in drug discovery programs by automated patch clamp. Frontiers in pharmacology 2014; 5: 203.
Yan JS, Chen M, Wang Q: New Drug Regulation and Approval in China. In A Comprehensive Guide to Toxicology in Preclinical Drug Development 2013; Elsevier Inc. pp. 713-23.
Erik Walum: Acute Oral Toxicity. Environmental Health Perspectives 1998; 106 (2): 497-503.
Teague SJ, Davis AM, Leeson PD, Oprea T: The Design of Leadlike Combinatorial Libraries Angewandte Chem. Int. Ed. 1999; 38(24): 3743-3748.
Alsanosi SM, Skiffington C, Padman S: Fundamental pharmacogenomics In Handbook of Pharmacogenomics and Stratified Medicine chapter 17 2014; 341-64.
Daniel F. Veber, Johnson SR, Cheng HY, Smith BR, Ward KW, and Kopple KD: Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. J. Med. Chem. 2002; 45:2615-23.
Brenk R, Schipani A, James D, Krasowski A, Gilbert IH, Frearson J, Wyatt PG: Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases. Chem Med Chem 2008; 3: 435 –44.
Lyder DL, Peter SR, Tinto WF, Bissada SM, McLean S, Reynolds WF: Minor Cassane Diterpenoids of Caesalpinia bonduc. J. Nat. Prod. 1998; 61: 1462-65.
Cox-Georgian D, Ramadoss N, Dona C, Basu C. Therapeutic and Medicinal Uses of Terpenes. Medicinal Plants 2019; 12: 333-59.
Nazir M, Saleem M, Tousif MI, Anwar MA, Surup F et al.: Meroterpenoids: A Comprehensive Update Insight on Structural Diversity and Biology. Biomolecules 2021; 11 (7): 1-61.
Khan RA, Hossain R, Siyadatpanah A, Al-Khafaji K, Ripon Khalipha AB, Dey D, et al.: Diterpenes/Diterpenoids and Their Derivatives as Potential Bioactive Leads against Dengue Virus: A Computational and Network Pharmacology Study. Molecules 2021; 26 (22): 1-29.
Published
Abstract Display: 374 
PDF Downloads: 374 
