In silico identification of natural fungicide from Melia azedarach against isocitrate lyase of Fusarium graminearum

Abstract

Isocitrate Lyase (ICL) is a crucial enzyme involved in the Glyoxylate pathway, essential for the virulence of several fungal pathogens including Fusarium graminearum. ICL is a novel target for the discovery of antifungal compounds and F. graminearum ICL inhibitors can be used to control the growth of this fungus. Although, several inhibitors of ICL have been identified, however, most of these inhibitors are not environment-friendly. Hence there is still a need to discover natural inhibitors of ICL that can be more effective. To identify a potential antifungal compound, we performed a structure‐based screening of phytochemicals of Melia azedarach against the FgICL structure by molecular docking and 104 ligands were found to have a better docking score as compared to the reference molecule. These compounds were assessed for drug-likeness and ADMET prediction. After molecular docking, drug-likeness and toxicity analysis, six potential compounds (Melianoninol (−6.6 kcal/mol), Nimbinene (−7.7 kcal/mol), Vilasinin (−8.1 kcal/mol), Fraxinellone (−6.7 kcal/mol), Gedunin (−7.8 kcal/mol), and Meldenin (−7.8 kcal/mol)) were subjected for rescoring by X-Score. The structural stability and dynamics of screened compounds at the active site of FgICL were examined using MD simulation and MM-PBSA analysis. The result of MM-PBSA revealed that four phytochemicals viz. Melianoninol, Nimbinene, Vilasinin, and Fraxinellone had binding free energy of −17.25 kcal/mol, −59.35 kcal/mol, −64.79 kcal/mol, and −29.86 kcal/mol, respectively. Molecular dynamics simulation and MM-PBSA demonstrated that these four phytochemicals displayed considerable significant structural and pharmacological properties and could be probable antifungal drug candidates against F. graminearum. These phyotchemicals of M. azedarach may be suitable candidates for further experimental analysis.

Communicated by Ramaswamy H. Sarma

Keywords:

• Anti-fungal
• M. azedarach
• F. graminearum
• isocitrate lyase
• docking
• X-Score
• ADMET
• MD simulation

Acknowledgements

The authors are thankful to the Head Department of Botany, Kumaun University, Nainital for providing the facility, space, and resources for this work. The Authors also acknowledge Kumaun University, Nainital for providing high-speed internet facilities. We also extend our acknowledge to Rashtriya Uchchattar Shiksha Abhiyan (RUSA), Ministry of Human Resource Development, Government of India to provide Computational infrastructure for the establishment of Bioinformatics Centre in Kumaun University, S. S. J Campus, Almora.

Disclosure statement

The authors declare that there is no conflict of interest regarding the publication of this paper.

Author contributions

Tanuja Joshi designed the protocol, conducted experiment, collected data, and prepared the manuscript. Tushar Joshi helps to analyze MD and post-MD simulation. Priyanka Sharma contributed to the construction and analysis of Ligplots. Hemlata Pundir collaborated in data collection for pharmacokinetic evaluation in the present study. Dr. Subhash Chandra guided in conducting experiment, methodology troubleshooting and reviewing of the manuscript.

Additional information

Funding

There was no funding source to carry out this research work.