TPS1 drug design for rice blast disease in magnaporthe oryzae

Abstract

Magnaporthe oryzae (M. oryzae) is a fungal pathogen and the causal agent of rice blast disease. Previous lipidomics analysis of M. oryzae demonstrated that trehalose, a carbohydrate common to various fungi and algae, is thought to be involved in the possible conversion of glycogen into triacylglycerides for energy, an important step in the pathogenesis of M. oryzae. A key enzyme responsible for trehalose synthesis is trehalose-6-phosphate synthase 1 (Tps1). Therefore, we modeled the structure of Tps1 and sought to screen a chemical database in silico for possible inhibitors of the enzyme. Based on homologous alignment and sequence analysis, we first modeled the structure of Tps1 to determine the potential active site of the enzyme and its conformation. Using this model, we then undertook a docking study to determine the potential interaction that would manifest between Tsp1 and potential chemical inhibitors. Of the 400,000 chemicals screened in the Molecular Libraries Small Molecule Repository, we identified 45 potential candidates. The best candidate (Compound 24789937) was chosen and subjected to various structural optimization techniques to improve the suitability of the potential chemical inhibitors at the docking site of Tps1. From these modified versions of Compound 24789937, one lead compound (Lead 25) was shown to have the best binding affinity to Tps1 and good water solubility as compared with the ideal template compound and the other 44 potential candidates. Molecular dynamics simulation further confirmed the strength of the Tps1–Lead 25 complex and indicated the potential for Lead 25 to be used as an inhibitor of Tps1 in the control of M. oryzae–mediated rice blast disease.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-18) contains supplementary material, which is available to authorized users.

Central Role of the Trehalose Biosynthesis Pathway in the Pathogenesis of Human Fungal Infections: Opportunities and Challenges for Therapeutic Development

“…There are already inhibitors of the trehalase enzymes, such as validamycin A, that have been identified (206). Many studies of plants and parasites have characterized the structure of trehalose-related enzymes to screen for small-molecule inhibitors (132,207). For example, Xue et al (207) characterized the structure of TPS1 from the plant pathogen Magnaporthe oryzae and screened for potential small-molecule inhibitors by using a chemical database in silico.…”

Efficacy of Aqueous Leaf Extract of Medicinal Plants against Blast and Brown Spot Disease of Rice

“…Many biotic stresses hamper rice production and specifically, fungal diseases cause huge economic losses (Kumar et al, 2009). Among these the seed-borne diseases mainly leaf blast caused by Magnaporthe oryzae represents a serious threat to global rice production (Xue et al, 2014), and brown spot caused by Bipolaris oryzae reduces rice yield and shows substantial global impact (Nejad et al, 2014)to the crop. The losses due to these diseases in developing countries are estimated to be 60-80% higher than in industrialized countries and conservatively estimated that they cause losses in the order of 50 million ton of food annually (Vishunavat, 2012).…”

Identification of Potential Nematicidal Compounds against the Pine Wood Nematode, Bursaphelenchus xylophilus through an In Silico Approach

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