In silico Prediction, Characterization, Molecular Docking, and Dynamic Studies on Fungal SDRs as Novel Targets for Searching Potential Fungicides Against Fusarium Wilt in Tomato

Abstract

Vascular wilt of tomato caused by Fusarium oxysporum f.sp. lycopersici (FOL) is one of the most devastating diseases, that delimits the tomato production worldwide. Fungal short-chain dehydrogenases/reductases (SDRs) are NADP(H) dependent oxidoreductases, having shared motifs and common functional mechanism, have been demonstrated as biochemical targets for commercial fungicides. The 1,3,6,8 tetra hydroxynaphthalene reductase (T4HNR) protein, a member of SDRs family, catalyzes the naphthol reduction reaction in fungal melanin biosynthesis. We retrieved an orthologous member of T4HNR, (complexed with NADP(H) and pyroquilon from Magnaporthe grisea) in the FOL (namely; FOXG_04696) based on homology search, percent identity and sequence similarity (93% query cover; 49% identity). The hypothetical protein FOXG_04696 (T4HNR like) had conserved T-G-X-X-X-G-X-G motif (cofactor binding site) at N-terminus, similar to M. grisea (1JA9) and Y-X-X-X-K motif, as a part of the active site, bearing homologies with two fungal keto reductases T4HNR (M. grisea) and 17-β-hydroxysteroid dehydrogenase from Curvularia lunata (teleomorph: Cochliobolus lunatus PDB ID: 3IS3). The catalytic tetrad of T4HNR was replaced with ASN115, SER141, TYR154, and LYS158 in the FOXG_04696. The structural alignment and superposition of FOXG_04696 over the template proteins (3IS3 and 1JA9) revealed minimum RMSD deviations of the C alpha atomic coordinates, and therefore, had structural conservation. The best protein model (FOXG_04696) was docked with 37 fungicides, to evaluate their binding affinities. The Glide XP and YASARA docked complexes showed discrepancies in results, for scoring and ranking the binding affinities of fungicides. The docked complexes were further refined and rescored from their docked poses through 50 ns long MD simulations, and binding free energies (ΔGbind) calculations, using MM/GBSA analysis, revealed Oxathiapiprolin and Famoxadone as better fungicides among the selected one. However, Famoxadone had better interaction of the docked residues, with best protein ligand contacts, minimum RMSD (high accuracy of the docking pose) and RMSF (structural integrity and conformational flexibility of docking) at the specified docking site. The Famoxadone was found to be acceptable based on in silico toxicity and in vitro growth inhibition assessment. We conclude that the FOXG_04696, could be employed as a novel candidate protein, for structure-based design, and screening of target fungicides against the FOL pathogen.

Computational Exploration of Phytochemicals as Potent Inhibitors of Acetylcholinesterase Enzyme in Alzheimer’s Disease

“…The lowest value of XP GScore is considered as the best value and is always appreciable [65,66,67,68]. In the MM-GBSA study, coptisine generated the lowest ΔGBind score of -49.91 Kcal/mol and the highest ΔGBind score of showed by naringenin was -23.73 Kcal/mol.…”

Computational Biology Approaches Revealing Novel Target in Vascular Wilt Pathogen Fusarium oxysporum f. sp. lycopersici for the Ligands of Marine Actinobacterial Origin

“…A Sequence of Short-chain Dehydrogenases/ Reductase (SDR) (FOXG_00472) in Fusarium oxysporum was retrieved from NCBI and modeled using dehydrogenase of Bacillus anthracis used as a template (PDB: 3I3OA) 12 . The model of SDR in Fusarium oxysporum was constructed by homology modeling through the prime module of Schrodinger 2018-4.…”

“…In the recent research set-up, numerous literatures narrate the production of antifungal compounds with pyrrole ring structures by a marine 10 and rhizosphere soil 11 actinobacteria belonging to the genus Streptomyces spp. Short-chain dehydrogenases/ reducatses (SDRs) are the essential enzymes of melanin biosynthetic pathways 12 . SDRs are responsible for the development of key virulent "factors" and contribute to the pathogenic behaviors such as appressorium formation, conidial germination, penetration, and propagation inside the host tissues 13 .…”

In silico approach of receptor-ligand binding and interaction: Established phytoligands from Tagetes errecta Linn. against bacterial β-glucosidase receptor

“…6 On the other hand, the molecular docking tool is used to predict the interaction between a small molecule (ligand) and a macromolecule (protein) that describes the behavioural characterization of small molecules in the binding site of target receptor. [6][7][8][9][10] It is an interesting research that natural compounds not only use in pharmaceuticals while can use for insecticides, pesticides, biofertilizers, etc. Among these, fungistatic is an important compound to prevent various fungal infection in which researchers are showing interest to inhibit the multiplication of fungal activities.…”