Construction Of A Molecular Target Database For Fungicides And Virtual Screening Of Hsp90 Inhibitor

Targets of fungicides are the important basis for the design,synthesis and development of new fungicides,and the study of drug targets has been the hot spot.Up to now,more than 400 fungicides have been developed for the control of plant diseases,but only 20 target proteins have been identified for these fungicides,among which there are only a few targets with important fungicide development and utilization value.In addition,the growing problem of fungicide resistance has forced researchers to search for novel fungicide targets.However,the scattered data sources and the lack of search and analysis tools have made access to these data difficult and their use inadequate.Therefore,pooling fungicide target-related resources,searching for proteins and verifying their potential target-forming properties are important to facilitate the discovery of novel fungicide targets,slow down the increasing drug resistance and create novel green pesticides.Firstly,we have developed a data-rich and user-friendly Fungicide Target Database(Fungi TAD)using a chemical bioinformatics approach.The database covers23 known fungicide targets,2,931 protein sequences,and 2,036 homology modeling structures,which were identified in 167 species.Each target contains detailed protein annotation information,including sequence,structure,function,species,corresponding fungicides,references and so on.In addition,we also performed homology modeling and molecular docking.This work not only helps researchers to quickly familiarize with the existing fungicide targets and fungicides,but also provides information technology support for the discovery of new fungicide targets and new ideas for potential pesticide target prediction.Secondly,during the data collection and study of fungicide targets,we found that Heat shock protein 90(Hsp90)plays an important role not only in controlling the normal growth of human cells and promoting tumor cell development,but also in plant development,response to stressful environments and disease resistance.More importantly,Fg Hsp90 has also been found to be an essential gene for Fusarium graminearum,and its delete is lethal to Fusarium graminearum.We screened two commercial small molecule libraries,Specs and Chem Div,using Hsp90 as the target protein using a virtual screening method with consistent docking and consistent scoring.By molecular dynamics simulations and protein-ligand interaction analysis,we selected and purchased 30 commercial compounds for bioactivity testing.Ultimately,we identified six active compounds with optimization potential.At the concentration of 20 μg/m L,compounds S558-0211,S558-0224,S929-4519,P207-9062,D754-0055,and P207-9065 showed some inhibition against Fusarium graminearum,with inhibition rates of 60.43%,59.99%,58.67%,58.67%,58.26%,57.33%;compounds T655-0536,S929-4519,S558-0211 showed some inhibitory effect on Fusarium oxysporum with inhibition rates of 60.41%,54.32%,45.18%;compound S558-0224 showed some inhibitory effect on Alternaria alternata with inhibition rates of 43.24%.This indicates that these compounds are able to act on plant pathogens and show a good biological phenotype,providing preliminary evidence of the potential target-forming properties of Hsp90 in the field of agricultural fungicides.