<i>In silico</i> identification of natural fungicide from <i>Melia azedarach</i> against isocitrate lyase of <i>Fusarium graminearum</i>

Isocitrate Lyase (ICL) is a crucial enzyme involved in the Glyoxylate pathway, essential for the virulence of several fungal pathogens including <i>Fusarium graminearum</i>. ICL is a novel target for the discovery of antifungal compounds and <i>F. graminearum</i> 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 <i>Melia azedarach</i> 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 <i>F. graminearum.</i> These phyotchemicals of <i>M. azedarach</i> may be suitable candidates for further experimental analysis. Communicated by Ramaswamy H. Sarma