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Current Molecular Medicine

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ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

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Research Article

Repurposing of Fluvastatin Against Candida albicans CYP450 Lanosterol 14 α-demethylase, a Target Enzyme for Antifungal Therapy: An In silico and In vitro Study

Author(s): Ritika Rana, Ruchika Sharma and Anoop Kumar*

Volume 19, Issue 7, 2019

Page: [506 - 524] Pages: 19

DOI: 10.2174/1566524019666190520094644

Price: $65

Abstract

Background: The incidence of fungal infections has increased significantly. Specifically the cases of candida albicans infection are increasing day by day and their resistance to clinically approved drugs is a major concern for humans. Various classes of antifungal drugs are available in the market for the treatment of these infections but unfortunately, none of them is able to treat the infection.

Objectives: Thus, in the present investigation, we have repurposed the well-known drug (Fluvastatin) in the treatment of Candida albicans infections by using in silico, in vitro and ex vivo techniques.

Material and Methods: Computational and in vitro techniques.

Results: Firstly, we developed and validated a simple model of CYP45014α-lanosterol demethylase of Candida albicans by using crystal structure of Mycobacterium tuberculosis (1EA1). Further, fluvastatin was docked with a validated model of CYP45014α-lanosterol demethylase and revealed good binding affinity as that of fluconazole. In vitro results (Percentage growth retardation, Fungal growth kinetics, Biofilm test and Post antifungal test) have shown good antifungal activity of fluvastatin. Finally, the results of MTT assay have shown non-cytotoxic effect of fluvastatin in murine splenocytes and thymocytes.

Conclusion: However, further in vivo studies are required to confirm the complete role of fluvastatin as an antifungal agent.

Keywords: Candida albicans, homologous model, fluvastatin, docking study, in vitro study, ex vivo study.

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[1]
Groll AH, Walsh TJ. Uncommon opportunistic fungi new nosocomial threats. Clin Microbiol Infect 2001; 7: 8-24.
[2]
Giraldo P, Von Nowakowski A, Gomes FA, et al. Vaginal colonization by Candida in asymptomatic women with and without a history of recurrent vulvovaginal candidiasis. Obstet Gynecol 2000; 95: 413-6.
[3]
Available at https://www.drugs.com data accessed on (2/4/18)
[4]
US Department of Health and Human Services (2012) Centers for Disease Control and Prevention (CDC). Antibiotic resistance threats in the United States. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf Accessed 23 Sept 2015
[5]
Jabra-Rizk MA, Falkler WA, Meiller TF. Fungal biofilms and drug resistance. Emerg Infect Dis 2004; 10: 14-9.
[6]
Rana R, Sharma R, Kumar A. Repurposing of Existing Statin drugs for treatment of Microbial Infections: How much promising?. Infec disord drug targets 2018.
[http://dx.doi.org/doi: 10.2174/1871526518666180806123230.]
[7]
Schmidt M, Dzogbeta S, Boyer MP. Inhibition of Candida albicans by Fluvastatin Is dependent on pH. Biochem Res Int 2009; 2009: 151424.
[8]
Nash JD, Burgess DS, Talbert RL. Effect of fluvastatin and pravastatin, HMG-CoA reductase inhibitors, on fluconazole activity against Candida albicans. Indian J Med Microbiol 2002; 51: 105-9.
[9]
Chin NX, Weitzman I, Della-Latta P. In vitro activity of fluvastatin, a cholesterol-lowering agent, and synergy with flucanazole and itraconazole against Candida species and Cryptococcus neoformans. Antimicrob Agents Chemother 1997; 41: 850-2.
[10]
Chaffin WL. Candida albicans cell wall proteins. Microbiol Mol Biol Rev 2008; 72: 495-544.
[11]
Podust LM, Poulos TL, Waterman MR. Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc Natl Acad Sci USA 2001; 98: 3068-73.
[12]
Hess B, Kutzner C, Van Der Spoel D, et al. GROMACS 4. Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 2014; 4: 435-47.
[13]
Kant K, Lal UR, Kumar A, Ghosh M. A merged molecular docking, ADME-T and dynamics approaches towards the genus of Arisaema as herpes simplex virus type 1 and type 2 inhibitors. Comput Bioland Chem 2019; 78: 217-26.
[14]
Essmann U, Perera L, Berkowitz M, et al. A smooth particle mesh Ewald method. J Phys Chem Biophys 1995; 103: 8577-93.
[15]
SchuÈttelkopf AW,Van Aalten DM. PRODRG a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallographica Section D. Acta Crystallogr 2004; 60: 1355-63.
[16]
Grant BJ, Rodrigues AP, ElSawy KM, et al. Bio3d: anR package for the comparative analysis of protein structures. BMC Bioinformatics 2006; 22: 2695-6.
[17]
Amadei A, Linssen A, Berendsen HJ. Essential dynamics of proteins. Proteins: Struct, Funct, Bioinf. Proteins 1993; 17: 412-25.
[18]
García AE. Large-amplitude nonlinear motions in proteins. Phys Rev Lett 1992; 68: 2696-700.
[19]
Balsera MA, Wriggers W, Oono Y, et al. Principal component analysis and long time protein dynamics. J Phys Chem B 1996; 100: 2567-72.
[20]
Himedialabs.com/TD/LQ508.pdf for tryptone soya broth (data accessed on 2/4/18).
[21]
Gupta M, Sharma R, Kumar A. Comparative potential of Simvastatin, Rosuvastatin and Fluvastatin against bacterial infection: an in silico and in vitro study. Orient Pharm Exp Med 2019; 1-17.
[22]
Wu WS, Chen CC, Chuang YC, et al. Efficacy of combination oral antimicrobial agents against biofilm-embedded methicillin-resistant Staphylococcus aureus. J Microbiol Immunol Infect 2013; 46: 89-95.
[23]
Kumar A, Sharma N. Comparative efficacy of piperine and curcumin in deltamethrin induced splenic apoptosis and altered immune functions. Pestic Biochem Physiol 2015; 119: 16-27.
[24]
Jacob KS, Ganguly S, Kumar P, et al. Homology model, molecular dynamics simulation and novel pyrazole analogs design of Candida albicans CYP450 lanosterol 14 α-demethylase, a target enzyme for antifungal therapy. J Biomol Struct Dyn 2017; 35: 1446-63.
[25]
Yang AS, Honig B. An integrated approach to the analysis and modeling of protein sequences and structures. III. A comparative study of sequence conservation in protein structural families using multiple structural alignments1. Biochem Mol Biol J 2000; 301: 691-711.
[26]
Rost B. Twilight zone of protein sequence alignments. Korean J Chem Eng 1999; 12: 85-94.
[27]
Meyer T, Ferrer-Costa C, Pérez A, et al. Essential dynamics: a tool for efficient trajectory compression and management. J Chem Theory Comput 2006; 2: 251-8.
[28]
Li W, Shen J, Liu G, et al. Exploring coumarin egress channels in human cytochrome P450 2A6 by random acceleration and steered molecular dynamics simulations. Proteins 2011; 79: 271-81.
[29]
Shen J, Li W, Liu G, et al. Computational insights into the mechanism of ligand unbinding and selectivity of estrogen receptors. J Phys Chem B 2009; 113: 10436-44.
[30]
Nygaard R, Zou Y, Dror RO, et al. The dynamic process of β2-adrenergic receptor activation. Cell 2013; 152: 532-42.
[31]
Kruse AC, Hu J, Pan AC, et al. Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nat 2012; 482: 552-9.
[32]
Lindorff-Larsen K, Piana S, Dror RO, et al. How fast-folding proteins fold. Sci 2011; 334: 517-20.
[33]
Piana S, Lindorff-Larsen K, Shaw DE. Atomic-level description of ubiquitin folding. Proc Natl Acad Sci USA 2013; 110: 5915-20.

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