Author(s):
Nahid Akhtar, Amit Joshi, Vikas Kaushik, Sangeetha Mohan, M. Amin-ul Mannan
Email(s):
mannan.phd@gmail.com , mohammad.20597@lpu.co.in
DOI:
10.52711/0974-360X.2023.00472 
Address:
Nahid Akhtar1, Amit Joshi2, Vikas Kaushik2, Sangeetha Mohan3, M. Amin-ul Mannan1
1Department of Molecular Biology and Genetics, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara - 144411, Punjab, India.
2Department of Bioinformatics, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara - 144411, Punjab, India.
3Department of Microbiology, Christian Medical College, Ludhiana - 141008, Punjab, India.
*Corresponding Author
Published In:
Volume - 16,
Issue - 6,
Year - 2023
ABSTRACT:
Candida auris is a rapidly emerging global public health concern. The increasing mortality in immunocompromised patients is mostly attributed to the rise of drug-resistant clinical isolates. Low bioavailability and toxicity of the existing antifungals further exacerbate the condition. Unfolded protein response (UPR) has been linked to fungal pathogenesis in previous studies. In this study the two hallmark proteins of the UPR pathway, Hac1p and Ire1p, were targeted to identify novel antifungals. Different phytochemicals showing various therapeutic potential were selected. Using various bioinformatics tools, the molecular property, bioactivity, toxicity, drug-likeness of these compounds were determined. The compounds showing the best properties were analyzed for their ability to interact with UPR proteins by molecular docking study. Finally, the molecular dynamics simulation analysis was performed to determine the stability of the interactions between the phytochemicals and the target protein. Flinderole-B, Drummondin-E, Betulinic acid, Ursolic acid, Oleanolic acid, Stigmasterol showed good drug-likeness scores. They were also found to be non-carcinogenic, and non-toxic; and followed Lipinski’s rule of five. Based on the simulation analysis Betulinic acid showed the best potential to target Hac1p while Drummondin-E showed the best potential to target Ire1p. Betulinic acid and Drummondin E could be potential inhibitors of the UPR pathway in C. auris. However, further in vitro and in vivo studies are needed to corroborate their antifungal potential.
Cite this article:
Nahid Akhtar, Amit Joshi, Vikas Kaushik, Sangeetha Mohan, M. Amin-ul Mannan. Betulinic acid and Drummondin E: Potential inhibitors of Unfolded Protein Response Pathway of Candida auris. Research Journal of Pharmacy and Technology 2023; 16(6):2867-2. doi: 10.52711/0974-360X.2023.00472
Cite(Electronic):
Nahid Akhtar, Amit Joshi, Vikas Kaushik, Sangeetha Mohan, M. Amin-ul Mannan. Betulinic acid and Drummondin E: Potential inhibitors of Unfolded Protein Response Pathway of Candida auris. Research Journal of Pharmacy and Technology 2023; 16(6):2867-2. doi: 10.52711/0974-360X.2023.00472 Available on: https://www.rjptonline.org/AbstractView.aspx?PID=2023-16-6-50
REFERENCES:
1. Brown GD. Denning DW. Gow NAR. Levitz SM. Netea MG. White TC. Hidden Killers: Human fungal infections. Science Translational Medicine. 2012;4(165):165rv13. doi.org/10.1126/scitranslmed.3004404
2. Kim JY. Human fungal pathogens: Why should we learn? Journal of Microbiology. 2016;54(3):145-148. doi.org/10.1007/s12275-016-0647-8
3. Turner SA. Butler G. The Candida pathogenic species complex. Cold Spring Harbor Perspectives in Medicine. 2014;4(9):a019778. doi.org/10.1101/cshperspect.a019778
4. Chowdhary A. Sharma C. Meis JF. Candida auris : A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally. PLoS Pathogens. 2017; 13(5):e1006290. doi.org/10.1371/journal.ppat.1006290
5. Candida auris | Candida auris | Fungal Diseases | CDC. Accessed August 22, 2019. https://www.cdc.gov/fungal/candida-auris/index.html
6. Cortegiani A. Misseri G. Fasciana T. Giammanco A. Giarratano A. Chowdhary A. Epidemiology, clinical characteristics, resistance, and treatment of infections by Candida auris. Journal of Intensive Care. 2018;6(1):69. doi.org/10.1186/s40560-018-0342-4
7. Thammahong A. Puttikamonkul S. Perfect JR. Brennan RG. Cramer RA. Central role of the trehalose biosynthesis pathway in the pathogenesis of human fungal infections: Opportunities and Challenges for Therapeutic Development. Microbiology and Molecular Biology Reviews. 2017;81(2): e00053. doi.org/10.1128/MMBR.00053-16
8. Singh S. Uppuluri P. Mamouei Z. Alqarihi A. Elhassan A. French S. Lockhart SR. Chiller T. Edwards JE. Ibrahim AS. The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection. PLoS Pathogens. 2019;15(8):e1007460. doi.org/10.1371/journal.ppat.1007460
9. Akhtar N. Joshi A. Kaushik V. Kumar M. Mannan MA. In-silico design of a multivalent epitope-based vaccine against Candida auris. Microbial Pathogenesis. 2021; 155:104879. doi: 10.1016/j.micpath.2021.104879
10. Miyazaki T. Kohno S. ER stress response mechanisms in the pathogenic yeast Candida glabrata and their roles in virulence. Virulence. 2014;5(2):365-370. doi.org/10.4161/viru.27373
11. Krishnan K. Askew DS. Endoplasmic reticulum stress and fungal pathogenesis. Fungal Biology Reviews. 2014;28(2-3):29-35. doi.org/10.1016/j.fbr.2014.07.001
12. Iracane E. Donovan PD. Ola M. Butler G. Holland LM. Identification of an exceptionally long intron in the HAC1. mSphere. 2018;3(6): e00532. doi.org/10.1128/mSphere.00532-18
13. Leitzmann C. Characteristics and health benefits of phytochemicals. Complementary Medicine Research. 2016;23(2):69-74. doi.org/10.1159/000444063
14. Akhtar N. Ayoubi R. Kour V. Gautam U. Mannan MA. Natural products, for fungal diseases management and prevention. The Natural Products Journal. 2022;12(2): e110521193310. doi.org/10.2174/2210315511666210512035847
15. Sharma K. Akhtar N. Upadhyay AK. Mannan MA. Efficacy of Trichoderma harzianum, a biocontrol agent for controlling opportunistic fungal pathogens. Journal of Pharmaceutical Sciences and Research. 2020;12(2):282-285.
16. Sarkar A. Akhtar N. Mannan MA. Antimicrobial property of cell wall lysed Chlorella, an edible alga. Research Journal of Pharmacy and Technology. 2021;14(7):3695-3699. doi.org/10.52711/0974-360X.2021.00639
17. Punasiya R. Dindorkar G. Pillai S. Antibacterial and antifungal activity of flower extract of Murraya paniculata L. Asian Journal of Research in Pharmaceutical Sciences. 2020;10(1):17-20. doi.org/10.5958/2231-5659.2020.00004.1
18. Saha D. Paul S. In vitro screening of antifungal activity of methanol extract of Plumbago indica L. against some pathogenic species of fungi. Asian Journal of Research in Pharmaceutical Sciences. 2012;2(2):55-57.
19. Singh AK. Singh A. Shaikh A. Singh R. Misra A. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes and Metabolic Syndrome: Clinical Research and Reviews. 2020;14(3):241-246. doi.org/10.1016/j.dsx.2020.03.011
20. Matkowski A. Kus P. Goralska E. Wozniak D. Mangiferin – a bioactive xanthonoid, not only from mango and not just antioxidant. Mini-Reviews in Medicinal Chemistry. 2013;13(3):439-455. doi.org/10.2174/1389557511313030011
21. Fernandez LS. Buchanan MS. Carroll AR. Feng YJ. Quinn RJ. Avery VM. Flinderoles A-C: Antimalarial bis-indole alkaloids from Flindersia species. Organic Letters. 2009;11(2):329-332. doi.org/10.1021/ol802506n
22. Jayasuriya H. Clark AM. McChesney JD. New antimicrobial filicinic acid derivatives from hypericum drummondii. Journal of Natural Products. 1991;54(5):1314-1320. doi.org/10.1021/np50077a013
23. Spina L. Cavallaro F. Fardowza NI. Lagoussis P. Bona D. Ciscato C. Rigante A. Vecchi M. Butyric acid: pharmacological aspects and routes of administration. Digestive and Liver Disease Supplements. 2007;1(1):7-11. doi.org/10.1016/S1594-5804(08)60004-2
24. Antonisamy P. Duraipandiyan V. Ignacimuthu S. Anti-inflammatory, analgesic and antipyretic effects of friedelin isolated from Azima tetracantha Lam. in mouse and rat models. Journal of Pharmacy and Pharmacology. 2011;63(8):1070-1077. doi.org/10.1111/j.2042-7158.2011. 01300.x
25. Kim S. Chen J. Cheng T. Gindulyte A. He J. He S. Li Q et al. PubChem 2019 update: improved access to chemical data. Nucleic Acids Research. 2018;47(D1): D1102-D1109. doi.org/10.1093/nar/gky1033
26. Lipinski CA. Lombardo F. Dominy BW. Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 2001;46(1-3):3-26. doi.org/10.1016/S0169-409X (00)00129-0
27. Yang H. Lou C. Sun L. Li J. Cai Y. Wang Z. Li W. Liu G. Tang Y. admetSAR 2.0: web-service for prediction and optimization of chemical ADMET properties. Bioinformatics. 2018;35(6):1067-1069. doi.org/10.1093/bioinformatics/bty707
28. Skrzypek MS. Binkley J. Binkley G. Miyasato SR. Simison M. Sherlock G. The Candida genome database (CGD): incorporation of Assembly 22, systematic identifiers and visualization of high throughput sequencing data. Nucleic Acids Research. 2016;45(D1): D592-D596. doi.org/10.1093/nar/gkw924
29. Yang J. Yan R. Roy A. Xu D. Poisson J. Zhang Y. The I-TASSER suite: Protein structure and function prediction. Nature Methods. 2014;12(1):7-8. doi.org/10.1038/nmeth.3213
30. Schneidman-Duhovny D. Inbar Y. Nussinov R. Wolfson HJ. PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Research. 2005;33(suppl_2): W363-W367. doi.org/10.1093/nar/gki481
31. Case DA. Cheatham TE. Darden T. Gohlke H. Luo R. Merz KM. Onufriev A et al. The Amber biomolecular simulation programs. Journal of Computational Chemistry. 2005;26(16):1668-1688. doi.org/10.1002/jcc.20290
32. Wang J. Wang W. Kollman PA. Case DA. Automatic atom type and bond type perception in molecular mechanical calculations. Journal of Molecular Graphics and Modelling. 2006;25(2):247-260. doi.org/10.1016/j.jmgm.2005.12.005
33. Toukmaji A. Sagui C. Board J. Darden T. Efficient particle-mesh Ewald based approach to fixed and induced dipolar interactions. Journal of Chemical Physics. 2000;113(24):10913-10927. doi.org/10.1063/1.1324708
34. Roe DR. Cheatham TE. PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. Journal of Chemical Theory and Computation. 2013;9(7):3084-3095. doi.org/10.1021/ct400341p
35. Guo F. Li SC. Wang L. Zhu D. Protein-protein binding site identification by enumerating the configurations. BMC Bioinformatics. 2012;13(1):158. doi.org/10.1186/1471-2105-13-158
36. Laskowski RA. Swindells MB. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. Journal of Chemical Information and Modeling. 2011;51(10):2778-2786. doi.org/10.1021/ci200227u
37. Jha A. Kumar A. multiple drug targeting potential of novel ligands against virulent proteins of Candida albicans. International Journal of Peptide Research and Therapeutics. 2020;26(2):921-942. doi.org/10.1007/s10989-019-09897-1
38. Domala R. Butti ARS. Eppakayla L. Study of antifungal activity of 2-Methyl-3-(5’-aryl/aryloxymethyl-1’, 3’, 4’-oxadiazol-2’-yl) amino-1, 8-naphthyridines. Research Journal of Pharmacy and Technology. 2022;15(2):757-760. doi.org/10.52711/0974-360X.2022.00126
39. Noshi SH. Basha M. Awad GEA. Elsayyad NME. Miconazole nitrate loaded Soluplus®-Pluronic® nano-micelles as promising drug delivery systems for ocular fungal infections: In vitro and in vivo considerations. Research Journal of Pharmacy and Technology. 2022;15(2):501-511. doi.org/10.52711/0974-360X.2022.00081
40. Deore SK. Surawase RK. Maru A. Formulation and evaluation of O/W nanoemulsion of ketoconazole. Research Journal of Pharmaceutical Dosage Forms and Technology. 2019;11(4):269-274. doi.org/10.5958/0975-4377.2019.00045.4
41. de Andrade Monteiro C. Ribeiro Alves dos Santos J. Phytochemicals and their antifungal potential against pathogenic yeasts. In Phytochemicals in human health. Edited by Rao V, Mans DRA and Rao L. IntechOpen, London. 2020. doi.org/10.5772/intechopen.87302
42. Parvatikar P. Saha B. Das SK. Reddy C. Bagali S. Kulkarni RV. Patil AV. Biradar MS. Das KK. Molecular docking identifies novel phytochemical inhibitors against SARS-COV-2 for Covid-19 therapy. Research Journal of Pharmacy and Technology. 2022;15(2):555-558. doi.org/10.52711/0974-360X.2022.00090
43. Sathyanarayan S. Pillai KS. Udhayakumar M. Subramaniam S. Molecular socking analysis of compounds from polyherbal powder against the proteins involved in diabetes mellitus. Research Journal of Pharmacy and Technology. 2022;15(2):859-862. doi.org/10.52711/0974-360X.2022.00143
44. Parameswari P. Devika R. In silico molecular docking studies of quercetin compound against anti-inflammatory and anticancer proteins. Research Journal of Pharmacy and Technology. 2019;12(11):5305-5309. doi.org/10.5958/0974-360X.2019.00919.3
45. Patadiya N. Vaghela V. Design, in-silico ADME study and molecular docking study of novel quinoline-4-on derivatives as factor Xa inhibitor as potential anti-coagulating agents. Asian Journal of Pharmaceutical Research. 2022;12(3):207-211. doi.org/10.52711/2231-5691.2022.00034
46. Otuokere IE. Amaku FJ. Alisa CO. In silico geometry optimization, excited – state properties of (2E)-N-hydroxy-3-[3-(phenylsulfamoyl) phenyl] prop-2-enamide (Belinostat) and its molecular docking studies with Ebola virus glycoprotein. Asian Journal of Pharmaceutical Research. 2015;5(3):131-137. doi.org/10.5958/2231-5691.2015.00020.9
47. Jha A. Vimal A. Bakht A. Kumar A. Inhibitors of CPH1-MAP kinase pathway: Ascertaining potential ligands as multi-target drug candidate in Candida albicans. International Journal of Peptide Research and Therapeutics. 2019;25(3):997-1010. doi.org/10.1007/s10989-018-9747-0
48. Akhtar N. Verma H. Silkari OM. Upadhyay AK. Kaushik V. Mannan MA. Drummondin E and Flinderole B are potential inhibitors of RNA-dependent RNA polymerase of SARS-CoV-2: an in-silico study. Biotechnologia. 2022;103(1):53-70. doi.org/10.5114/bta.2022.113915