Rational Design of Chitin Deacetylase Inhibitors for Sustainable Agricultural Use Based on Molecular Topology

Abstract

Fungicide resistance is a major concern in modern agriculture; therefore, there is a pressing demand to develop new, greener chemicals. Chitin is a major component of the fungal cell wall and a well-known elicitor of plant immunity. To overcome chitin recognition, fungal pathogens developed different strategies, with chitin deacetylase (CDA) activity being the most conserved. This enzyme is responsible for hydrolyzing the N-acetamido group in N-acetylglucosamine units of chitin to convert it to chitosan, a compound that can no longer be recognized by the plant. In previous works, we observed that treatments with CDA inhibitors, such as carboxylic acids, reduced the symptoms of cucurbit powdery mildew and induced rapid activation of chitin-triggered immunity, indicating that CDA could be an interesting target for fungicide development. In this work, we developed an in silico strategy based on QSAR (quantitative structure-activity relationship) and molecular topology (MT) to discover new, specific, and potent CAD inhibitors. Starting with the chemical structures of few carboxylic acids, with and without disease control activity, three predictive equations based on the MT paradigm were developed to identify a group of potential molecules. Their fungicidal activity was experimentally tested, and their specificity as CDA inhibitors was studied for the three best candidates by molecular docking simulations. To our knowledge, this is the first time that MT has been used for the identification of potential CDA inhibitors to be used against resistant powdery mildew strains. In this sense, we consider of special interest the discovery of molecules capable of stimulating the immune system of plants by triggering a defensive response against fungal species that are highly resistant to fungicides such as powdery mildew.

Rational Design of a Potential New Nematicide Targeting Chitin Deacetylase

“…As indicated above, CDA inhibitors previously identified for their abilities to suppress fungal diseases and obtained by a molecular topology approach were tested against the model nematode C. elegans to explore the possibility that CDA inhibitors may also target nematode CDA.…”

“…Inhibitors. As indicated above, CDA inhibitors previously identified for their abilities to suppress fungal diseases and obtained by a molecular topology approach 17 were tested against the model nematode C. elegans to explore the possibility that CDA inhibitors may also target nematode CDA. Table S1 shows the nematicidal effect on C. elegans of the fungal chitin deacetylase inhibitors identified by molecular topology.…”

“…Ideally, QSAR could be used to design new compounds that effectively target the chitin modification pathway in nematodes, CDA to be precise, leading to their death. 17 In the present work, the authors developed a molecular topology QSAR-based strategy to rationally design novel nematicides with CDA inhibitory activity.…”

“…In this last group stands quantitative structure–activity relationship (QSAR), which is a computational method used in agrochemistry to design and predict the activity of new chemical compounds. Ideally, QSAR could be used to design new compounds that effectively target the chitin modification pathway in nematodes, CDA to be precise, leading to their death . In the present work, the authors developed a molecular topology QSAR-based strategy to rationally design novel nematicides with CDA inhibitory activity.…”

“…The value of this kind of descriptors is not altered by the specific molecule 3D conformation. − To develop the QSAR strategy, the authors started from the initial data set of fungal CDA inhibitors identified in a previous work (Table S1). Starting from the hypothesis that CDA is also present in nematodes, which are chitin-containing organisms, a set of experiments on nematode Caenorhabditis elegans were carried out to determine the nematicide activity of the 20 compounds previously identified as fungal CDA inhibitors. From an overall of 20 compounds, six resulted to be active on nematodes.…”