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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 | ||
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