| تعداد نشریات | 24 |
| تعداد شمارهها | 929 |
| تعداد مقالات | 8,346 |
| تعداد مشاهده مقاله | 16,802,822 |
| تعداد دریافت فایل اصل مقاله | 14,117,251 |
Computational insights into fluconazole resistance by the suspected mutations in lanosterol 14α-demethylase (Erg11p) of Candida albicans | ||
| Molecular Biology Research Communications | ||
| دوره 9، شماره 4، 2020، صفحه 155-167 اصل مقاله (913.36 K) | ||
| نوع مقاله: Original article | ||
| شناسه دیجیتال (DOI): 10.22099/mbrc.2020.36298.1476 | ||
| نویسندگان | ||
| Sagunthala Murugesan Udaya Prakash1؛ Yasin Nazeer2؛ Sivaraman Jayanthi3؛ Mohammad Anaul Kabir* 1 | ||
| 1Molecular Genetics Laboratory, School of Biotechnology, National Institute of Technology Calicut, Calicut 673601, Kerala, India | ||
| 2Regional Medical Research Centre, Indian Council of Medical Research (ICMR), Belagavi -590010, Karnataka, India | ||
| 3Computational Drug Design Lab, School of BioSciences and Technology, Vellore Institute of Technology, Vellore-632014, Tamil Nadu, India | ||
| چکیده | ||
| Mutations in the ergosterol biosynthesis gene 11 (ERG11) of Candida albicans have been frequently reported in fluconazole-resistant clinical isolates. Exploring the mutations and their effect could provide new insights into the underlying mechanism of fluconazole resistance. Erg11p_Threonine285Alanine (Erg11p_THR285ALA), Erg11p_Leucine321Phenylalanine (Erg11p_LEU321PHE) and Erg11p_Serine457Proline (Erg11p_SER457PRO) are three fluconazole-resistant suspected mutations reported in clinical isolates of C. albicans. Therefore, our study aims to investigate the role of these suspected mutations in fluconazole resistance using in-silico methods. Molecular dynamics simulation (MDS) analysis of apo-protein for 25ns (nanosecond) showed that suspected mutant proteins underwent slight conformational changes in the tertiary structure. Molecular docking with fluconazole followed by binding free energy analysis showed reduced non-bonded interactions with loss of heme interaction and the least binding affinity for Erg11p_SER457PRO mutation. MDS of suspected mutant proteins-fluconazole complexes for 50ns revealed that Erg11p_SER457PRO and Erg11p_LEU321PHE have clear differences in the interaction pattern and loss or reduced heme interaction compared to wild type Erg11p-fluconazole complex. MDS and binding free energy analysis of Erg11p_SER457PRO-fluconazole complex showed the least binding similar to verified mutation Erg11p_TYR447HIS-fluconazole complex. Taken together, our study concludes that suspected mutation Erg11p_THR285ALA may not have any role whereas Erg11p_LEU321PHE could have a moderate role. However, Erg11p_SER457PRO mutation has a strong possibility to play an active role in fluconazole resistance of C. albicans. | ||
| کلیدواژهها | ||
| Candida albicans؛ Drug resistance؛ Suspected mutations؛ Molecular docking | ||
|
سایر فایل های مرتبط با مقاله
|
||
| مراجع | ||
|
1. Delaloye J, Calandra T. Invasive candidiasis as a cause of sepsis in the critically ill patient. Virulence 2014;5:154-162. 2. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, Gomersall Ch, Sakr Y, Reinhart K, EPIC II Group of Investigators. International study of the prevalence and outcomes of infection in intensive care units. Jama 2009;302:2323-2329. 3. Kullberg BJ, Arendrup MC. Invasive Candidiasis. N Engl J Med 2015;373:1445-1456. 4. Sanglard D. Emerging threats in antifungal resistant fungal pathogens. Front Med 2016;3:11. 5. Flowers SA, Colón B, Whaley SG, Schuler MA, David Rogers P. Contribution of clinically derived mutations in ERG11 to azole resistance in Candida albicans. Antimicrob Agents Chemother 2015;59:450-460. 6. Scorzoni L, de Paula e Silva ACA, Marcos CM, Assato PA, de Melo WC, de Oliveira HC, Costa-Orlandi CB, Mendes-Giannini MJ, Fusco-Almeida AM. Antifungal therapy: new advances in the understanding and treatment of mycosis. Front Microbiol 2017;8:36. 7. Aier I, Varadwaj PK, Raj U. Structural insights into conformational stability of both wild-type and mutant EZH2 receptor. Sci Rep 2016;6:1-10. 8. Ying Y, Zhao Y, Hu X, Cai Z, Liu X, Jin G, Zhang J, Zhang J, Liu J, Huang X. In-vitro fluconazole susceptibility of 1,903 clinical isolates of Candida albicans and the identification of ERG11 mutations. Microb Drug Resist 2013;19:266-273. 9. Carvalho VO, Okay TS, Melhem MSC, Szeszs MW, del Negro GMB. The new mutation L321F in Candida albicans ERG11 gene may be associated with fluconazole resistance. Rev Iberoam Micol 2013;30:209-212. 10. Wang B, Huang LH, Zhao JX, Wei M, Fang H, Wang DY, Wang HF, Yin JG, Xiang M. ERG11 mutations associated with azole resistance in Candida albicans isolates from vulvovaginal candidosis patients. Asian Pac J Trop Biomed 2015;5:909-914. 11. Alvarez-Rueda N, Fleury A, Morio F, Pagniez F, Gastinel L, Le Pape P. Amino acid substitutions at the major insertion loop of Candida albicans sterol 14alpha-demethylase are involved in fluconazole resistance. PLoS One 2011;6:e21239. 12. Morio F, Loge C, Besse B, Hennequin C, Le Pape P. Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature. Diagn Microbiol Infect Dis 2010: 66:373-384. 13. Keniya MV, Sabherwal M, Wilson RK, Woods MA, Sagatova AA, Tyndall JDA, Monk BC. Crystal structures of full-length lanosterol 14α-demethylases of prominent fungal pathogens Candida albicans and Candida glabrata provide tools for antifungal discovery. Antimicrob Agents Chemother 2018;62:e01134-18. 14. Caira MR, Alkhamis KA, Obaidat RM. Preparation and crystal characterization of a polymorph, a monohydrate, and an ethyl acetate solvate of the antifungal fluconazole. J Pharm Sci 2004;93:601-611. 15. Li W, Cowley A, Uludag M, Gur T, McWilliam H, Squizzato S, Park YM, Buso N, Lopez R. The EMBL-EBI bioinformatics web and programmatic tools framework. Nucleic Acids Res 2015;43:W580-W584. 16. Mcwilliam H, Li W, Uludag M, Squizzato S, Park YM, Buso N, Cowley AP, Lopez R. Analysis tool web services from the EMBL-EBI. Nucleic Acids Res 2013;41:W597-W600. 17. Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H, Remmert M, Söding J, Thompson JD, Higgins DG. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 2011;7:539. 18. Sagatova AA, Keniya MV, Wilson RK, Sabherwal M, Tyndall JDA, Monk BC. Triazole resistance mediated by mutations of a conserved active site tyrosine in fungal lanosterol 14α-demethylase. Sci Rep 2016;6:1-11. 19. Jacobson MP, Friesner RA, Xiang Z, Honig B. On the role of the crystal environment in determining protein side-chain conformations. J Mol Biol 2002;320:597-608. 20. Jacobson MP, Pincus DL, Rapp CS, Day TJF, Honig B, Shaw DE, Friesner RA. A hierarchical approach to all-atom protein loop prediction. Proteins 2004;55:351-367. 21. Greenwood JR, Calkins D, Sullivan AP, Shelley JC. Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution. J Comput Aid Mol Des 2010;24:591–604 22. Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya M. Epik: A software program for pKa prediction and protonation state generation for drug-like molecules. J Comput Aid Mol Des 2007;21:681-691. 23. Xiang MJ, Liu JY, Ni PH, Wang Sh, Shi C, Wei B, Ni YX, Ge HL. Erg11 mutations associated with azole resistance in clinical isolates of Candida albicans. FEMS Yeast Res 2013;13:386-393. 24. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. J Comput Aid Mol Des 2013;27:221-234. 25. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 2004;47:1739-1749. 26. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006;49:6177-6196. 27. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 2004;47:1750-1759. 28. Bowers KJ, Sacerdoti FD, Salmon JK, Shan Y, Shaw DE, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepeis JL, Kolossvary I, Moraes MA. Molecular dynamics scalable algorithms for molecular dynamics simulations on commodity clusters. Proceedings of the 2006 ACM/IEEE conference on Supercomputing - SC ’06. 29. Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput 2010;6:1509-1519. 30. Steinbrecher T, Zhu C, Wang L, Abel R, Negron C, Pearlman D, Feyfant E, Duan J, Sherman W. Predicting the effect of amino acid single-point mutations on protein stability large-scale validation of MD-based relative free energy calculations. J Mol Biol 2017;429:948-963. 31. Sidler D, Riniker S. Fast Nosé–Hoover thermostat: molecular dynamics in quasi-thermodynamic equilibrium. Phys Chem Chem Phys 2019;21:6059-6070. 32. Li J, Abel R, Zhu K, Cao Y, Zhao S, Friesner RA. The VSGB 2.0 model: A next generation energy model for high resolution protein structure modeling. Proteins 2011;79:2794-2812. 33. Zhu K, Shirts MR, Friesner RA. Improved methods for side chain and loop predictions via the protein local optimization program: variable dielectric model for implicitly improving the treatment of polarization effects. J Chem Theory Comput 2007;3:2108-2119. | ||
|
آمار تعداد مشاهده مقاله: 3,885 تعداد دریافت فایل اصل مقاله: 3,515 |
||
