Skip to main content
SpringerLink
Log in

In Silico Analog Design for Terbinafine Against Trichophyton rubrum: A Preliminary Study

  • Original Article
  • Published:
Indian Journal of Microbiology Aims and scope Submit manuscript

Abstract

The diseases caused by dermatophytes are common among several other infections which cause serious threat to human health. It is evident that enzyme squalene epoxidase is responsible for prolonged dermatophyte infection and it is appealing to note that this enzyme is also responsible for fatty acid synthesis in these groups of fungi. In the present study, terbinafine drug which targets enzyme squalene epoxidase has been explored to design its various novel analogues. The present study suggests that many more prominent drug analogues could be constituted which may be crucial towards designing new drug candidates. In the present study, we have designed a series of such analogues viz. [(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)(naphthalen-1-ylmethyl)amine, N-[8-({[(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)amino}methyl)naphthalen-1-yl]-2-(sulfoamino) acetamide, {[4-(dihydroxyamino)-8-({[(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)amino}methyl)naphthalen-1-yl]sulfanyl}methanol and (R)-{[4-({[(2E,6R)-6,7-dimethyloct-2-en-4-yn-1-yl](methyl)amino}methyl)-5-[(hydroxysulfamoyl)amino]naphthalen-1-yl]amino}sulfinic acid. Moreover, further by molecular docking approach the binding between enzyme and designed analogues was further analysed. The present preliminary report suggested a considerably good docking interaction score of −338.75 kcal/mol between terbinafine and squalene epoxidase from Trichophyton rubrum. This preliminary study implies that few designed candidate ligands can be effectual towards the activity of this enzyme and can play crucial role in pathogenesis control of T. rubrum.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Wang W, Chunquan S, Xiaoying C, Haitao J, Zhenyuan M, Jianzhong Y, Wannian Z (2009) Design, synthesis, and antifungal activity of novel conformationally restricted triazole derivatives. Arch Pharm Chem Life Sci 342:732–739. doi:10.1002/ardp.200900103

    Article  CAS  Google Scholar 

  2. Cheung RC, Wong JH, Pan WL, Chan YS, Yin CM, Dan XL, Wang HX, Fang EF, Lam SK, Ngai PH, Xia LX, Liu F, Ye XY, Zhang GQ, Liu QH, Sha O, Lin P, Ki C, Bekhit AA, Ael-D Bekhit, Wan DC, Ye XJ, Xia J, Ng TB (2014) Antifungal and antiviral products of marine organisms. Appl Microbiol Biotechnol 98:3475–3494. doi:10.1007/s00253-014-5575-0

    Article  CAS  PubMed  Google Scholar 

  3. Regina L, Sandra F, Vlasta K, Natascha S, Eva P, Kathrin W, Mojca L, Karina L, Christoph R, Ivan H, Friederike T (2003) Molecular mechanism of terbinafine resistance in Saccharomyces cerevisiae. Antimicrob Agents Chemother 47:3890–3900. doi:10.1128/AAC.47.12.3890-3900.2003

    Article  Google Scholar 

  4. Favre B, Ryder NS (1996) Characterization of squalene epoxidase activity from the dermatophyte Trichophyton rubrum and its inhibition by terbinafine and other antimycotic agents. Antimicrob Agents Chemother 40:443–447

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Marcin N, Marcin H, Lucjan SW, Piotr S, Dariusz MP, Michal L, Krzysztof G, Leszek R (2011) Detailed mechanism of squalene epoxidase inhibition by terbinafine. J Chem Inf Model 51:455–462. doi:10.1021/ci100403b

    Article  Google Scholar 

  6. Petranyi G, Meingassner JG, Mieth H (1987) Antifungal activity of the allylamine derivative terbinafine in vitro. Antimicrob Agents Chemother 31:1365–1368. doi:10.1128/AAC.31.9.1365

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. de Ludmila MB, Patrícia CS, Talles PP, Milene AR, Patrícia SC, Danielle GS, Daniel AS (2013) IFN-γ impairs Trichophyton rubrum proliferation in a murine model of dermatophytosis through the production of IL-1β and reactive oxygen species. Med Mycol 52:293–302. doi:10.1093/mmy/myt011

    Google Scholar 

  8. Tuukka S, Teijo IS, Nora MH, Janne TB, Pertti JN, Mika S, Klaus TO, Kari L (2015) Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol. Eur J Clin Pharmacol. doi:10.1007/s00228-014-1799-2

    Google Scholar 

  9. Bhakti P, Meena AK, Pissurlenkar R, Mamata J, Evans CC, Sudha S (2010) Probing molecular level interaction of antifungal drugs with model membranes by molecular modeling, multinuclear NMR and DSC methods. Int J Cur Pharm Res 2:47–56

    Google Scholar 

  10. Prashant SK, Meenakshi ND, Vithal MK (2008) Design, synthesis, antifungal activity, and ADME prediction of functional analogues of terbinafine. Med Chem Res 18:421–432. doi:10.1007/s00044-008-9138-8

    Google Scholar 

  11. Che X, Sheng C, Wang W, Cao Y, Xu Y, Ji H, Dong G, Miao Z, Yao J, Zhang W (2009) New azoles with potent antifungal activity: design, synthesis and molecular docking. Eur J Med Chem 44:4218–4226. doi:10.1016/j.ejmech.2009.05.018

    Article  CAS  PubMed  Google Scholar 

  12. Francis G, Remi G, Cedric L, Fabrice P, Carine P, Marc LB, Patrice LP (2009) Synthesis and structure–activity relationships of 2-phenyl-1-[(pyridinyland piperidinylmethyl)amino]-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents. Bioorg Med Chem Lett 19:301–304. doi:10.1016/j.bmcl.2008.11.101

    Article  Google Scholar 

  13. Nalu TAP, Fernanda CAM, Antonio R, Nilce MMR (2010) Dermatophytes: host-pathogen interaction and antifungal resistance. An Bras Dermatol 85:657–667

    Article  Google Scholar 

  14. Yan Z, Shichong Y, Renwu L, Qingjie Z, Xiang L, Maocheng W, Ting H, Xiaoxun C, Honggang Hu, Qiuye W (2014) Synthesis, antifungal activities and molecular docking studies of novel 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates. Eur J Med Chem 74:366–374. doi:10.1016/j.ejmech.2014.01.009

    Article  Google Scholar 

  15. Nalu TAP, Pablo RS, Juliana PF, Henrique CSS, Fernanda GP, Fernanda CAM, Diana EG, Fernando S, Rodrigo AC, Mendelson M, Jeny RCS, Roseli AF, Antonio R, Nilce MMR (2010) Transcriptional profiling reveals the expression of novel genes in response to various stimuli in the human dermatophyte Trichophyton rubrum. BMC Microbiol 10:39. doi:10.1186/1471-2180-10-39

    Article  Google Scholar 

  16. Anke B, Ekaterina S, Gernot G, Christoph H, Susann S, Peter S, Andrew H, Marius F, Andreas P, Karol S, Marc F, Ivo P, Steffen P, Marco G, Robert W, Wenjun L, Olaf K, Volker S, Christian H, Bernhard H, Theodore CW, Matthias P, Reinhard G, Joseph H, Johannes W, Peter FZ, Michel M, Axel AB (2011) Comparative and functional genomics provide insights into the pathogenicity of dermatophytic fungi. Genom Biol 12:R7. doi:10.1186/gb-2011-12-1-r7

    Article  Google Scholar 

  17. Karthik MVK, Satya Deepak MVKN, Shukla P (2012) Explication of interactions between HMGCR isoform 2 and various statins through In silico modeling and docking. Comp Biol Med 42:156–163. doi:10.1016/j.compbiomed.2011.11.003

    Article  CAS  Google Scholar 

  18. Singh PK, Shukla P (2012) Molecular modeling and docking of microbial inulinases towards perceptive enzyme-substrate interactions. Ind J Microbiol 52:373–380. doi:10.1007/s12088-012-0248-0

    Article  CAS  Google Scholar 

  19. Osborne CS, Leitner I, Favre B, Ryder NS (2005) Amino acid substitution in Trichophyton rubrum squalene epoxidase associated with resistance to terbinafine. Antimicrob Agents Chemother 49:2840–2844

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Yang Z (2008) I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9:40. doi:10.1186/1471-2105-9-40

    Article  CAS  Google Scholar 

  21. Dong X, Yang Z (2011) Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization. Biophys J 101:2525–2534. doi:10.1016/j.bpj.2011.10.024

    Article  Google Scholar 

  22. Bhattacharya A, Tejero R, Montelione GT (2007) Evaluating protein structures determined by structural genomics consortia. Proteins 66:778–795. doi:10.1002/prot.21165

    Article  CAS  PubMed  Google Scholar 

  23. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M (2008) DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucl Acids Res 36:D901–D906. doi:10.1093/nar/gkm958

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Marcus DH, Donald EC, David CL, Tim V, Eva Z, Geoffrey RH (2012) Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J Cheminformatics 4:17. doi:10.1186/1758-2946-4-17

    Article  Google Scholar 

  25. Lagorce D, Maupetit J, Baell J, Sperandio O, Tuffery P, Miteva MA, Galons H, Villoutreix BO (2011) The FAF-Drugs2 server: a multistep engine to prepare electronic chemical compound collections. Bioinformatics 27:2018–2020. doi:10.1093/bioinformatics/btr333

    Article  CAS  PubMed  Google Scholar 

  26. Macindoe G, Mavridis L, Venkatraman V, Devignes MD, Ritchie DW (2010) HexServer: an FFT-based protein docking server powered by graphics processors. Nucl Acids Res 38:W445–W449. doi:10.1093/nar/gkq311

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Dessalew N, Bharatam PV (2007) 3D-QSAR and molecular docking study on bisarylmaleimide series as glycogen synthase kinase 3, cyclin dependent kinase 2 and cyclin dependent kinase 4 inhibitors: an insight into the criteria for selectivity. Eur J Med Chem 42:1014–1027. doi:10.1016/j.ejmech.2007.01.010

    Article  CAS  PubMed  Google Scholar 

  28. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623. doi:10.1021/jm020017n

    Article  CAS  PubMed  Google Scholar 

  29. Steven B, Gilbert JB, Michael M (1978) Potential inhibitors of l-asparagine biosynthesis. 4. Substituted sulfonamide and sulfonylhydrazide analogs of l-asparagine. J Med Chem 978:45–49. doi:10.1021/jm00199a008

    Google Scholar 

Download references

Acknowledgments

We hereby acknowledge BTIS-Sub DIC facility at BIT Mesra through DBT, GOI and the Department of Agriculture, Government of Jharkhand for financial support for our department towards infrastructure facilities.

Author information

Authors and Affiliations

  1. Enzyme Technology and Protein Bioinformatics Laboratory, Department of Microbiology, Maharshi Dayanand University, Rohtak, 124001, Haryana, India

    Puneet Kumar Singh & Pratyoosh Shukla

  2. Department of Biotechnology, Birla Institute of Technology (Deemed University), Mesra, Ranchi, 835215, India

    Sudha Karumuri

Authors
  1. Sudha Karumuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Puneet Kumar Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pratyoosh Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pratyoosh Shukla.

Additional information

The authors Sudha Karumuri and Puneet Kumar Singh should be regarded as the joint first authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karumuri, S., Singh, P.K. & Shukla, P. In Silico Analog Design for Terbinafine Against Trichophyton rubrum: A Preliminary Study. Indian J Microbiol 55, 333–340 (2015). https://doi.org/10.1007/s12088-015-0524-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12088-015-0524-x

Keywords

Search

Navigation