Homology Modeling and Pharmacophore Based Inhibitor Design Targeting Isocitrate Lyase of Madurella mycetomatis-A...

Eumycetoma, caused by pathogenic fungi, is one of the most neglected tropical disease worldwide. The causative agent of the disease is Madurella mycetomatis. Ethnomedicinal sources reveal that several medicinal plants are used for the phytotherapeutic management of eumycetoma symptoms. M. mycetomatis uses isocitrate lyase (ICL) to promote gluconeogenesis for growth and survival in adverse host conditions. This study aims to develop a natural inhibitor molecule of ICL to target against M. mycetomatis using computational techniques. Homology modeling was used to predict the 3D structure of ICL using Magnaporthe oryzae as a template (85.80% similarity). A dataset of 100 unique phytochemicals were screened based on their docking score in comparison with the natural substrate isocitrate. Pharmacophore modeling was performed to generate the lead molecule which was further optimized using scaffold optimization. The molecule was further supported by quantitative structure-activity relationship (QSAR) analysis. A retrosynthetic approach was also employed to assess synthetic feasibility. Molecular dynamics simulations indicated structural stability, and the predicted molecule exhibited higher binding affinity than the substrate, suggesting potential competitive inhibition of ICL.