Highly potent natural fungicides identified in silico against the cereal killer fungus Magnaporthe oryzae

Abstract

Magnaporthe oryzae is one of the most notorious fungal pathogens that causes blast disease in cereals, and results in enormous loss of grain production. Many chemical fungicides are being used to control the pathogen but none of them are fully effective in controlling blast disease. Therefore, there is a demand for the discovery of a new natural biofungicide to manage the blast disease efficiently. A large number of new natural products showed inhibitory activities against M. oryzae in vitro. To find out effective biofungicides, we performed in silico molecular docking analysis of some of the potent natural compounds targeting four enzymes namely, scytalone dehydratase, SDH1 (PDB ID:1STD), trihydroxynaphthalene reductase, 3HNR (PDB ID:1YBV), trehalose-6-phosphate synthase, Tps1 (PDB ID:6JBI) and isocitrate lyase, ICL1 (PDB ID:5E9G) of M. oryzae fungus that regulate melanin biosynthesis and/or appresorium formation. Thirty-nine natural compounds that were previously reported to inhibit the growth of M. oryzae were subjected to rigid and flexible molecular docking against aforementioned enzymes followed by molecular dynamic simulation. The results of virtual screening showed that out of 39, eight compounds showed good binding energy with any one of the target enzymes as compared to reference commercial fungicides, azoxystrobin and strobilurin. Among the compounds, camptothecin, GKK1032A2 and chaetoviridin-A bind with more than one target enzymes of M. oryzae. All of the compounds except tricyclazole showed good bioactivity score. Taken together, our results suggest that all of the eight compounds have the potential to develop new fungicides, and remarkably, camptothecin, GKK1032A2 and chaetoviridin-A could act as multi-site mode of action fungicides against the blast fungus M. oryzae.

In-silico prediction of highly promising natural fungicides against the destructive blast fungus Magnaporthe oryzae

“…Molecular docking simulations were used to clarify the compounds' binding mode and obtain other information that could be utilized for further structural optimization [ 16 , 57 ]. Optimum binding affinity is achieved by lowering binding free energy between the target protein and the lead compound through optimization [ 13 , 24 , 37 ]. Our selected 39 antifungal natural products and reference fungicide (azoxystrobin and strobilurin) compounds were docked against the two different target proteins, single-stranded DNA binding protein (4AGH) and effector protein (6R8M) ( Fig.…”

“…1STD (Cryptocin, Tanzawaic-acid-L, Camptothecin, HDFO), 1YBV (Alternariol-monomethyl-ether, GKK1032A2, Arohynapene-A, Camptothecin, Tricyclazole), 6JBI (Chaetoviridin-A, GKK1032A2, Camptothecin, Rocaglaol), 5E9G (Arohynapene-B, Pannellin) etc. were retrieved from the PubChem database [ 9 , 24 ], and their 3D structures were generated using Online SMILES Translator and Structure File Generator [ 43 ]. Afterward, each compound was ready as ligand for molecular docking study with the target proteins.…”

“…It is possible to quantify experimentally the strength of an interaction between a protein and ligand based on the free energy of binding through computational method using 3D structures. According to the pharmacology, it is well-known that if an enzymes active site is blocked by ligand, its functional activity will be terminated [ 24 ]. The active site of the proteins was identified before going to the molecular docking simulation study through metaPocket ( https://projects.biotec.tu-dresden.de/metapocket/ ) and cross-checked by another server named CASTp ( http://sts.bioe.uic.edu/castp/index.html?2r7g ).…”

“…The Berendsen thermostat, together with constant temperature and pressure were used in the simulations for 100 ns (ns). Through the investigation of the simulation trajectory data, the root-mean-square deviation (RMSD), root-mean-square-fluctuation (RMSF), radius of gyration (Rg), hydrogen bond, and solvent-accessible surface area (SASA) were assessed [ 24 , 37 ].…”

“…Due to the rapid speed in evolution of the pathogen, traditional breeding strategies take more time to develop resistance [ 18 , 52 ]. Therefore, development of new fungicides using bioactive natural compounds with novel mode of actions is a promising approach to managing blast disease [ 24 ]. Research has been conducted to discover the antifungal natural compounds against blast fungus in vitro , but filed efficacy and mode of action of most of these compounds are unclear [ 6 , 7 , 64 ].…”