Soybean-associated endophytic fungi as potential source for anti-COVID-19 metabolites supported by docking analysis.

AIMS: To identify the metabolites produced by the endophytic fungus, Aspergillus terreus and to explore the anti-viral activity of the identified metabolites against the pandemic disease COVID-19 in-silico. METHODS AND RESULTS: Herein, we reported the isolation of A. terreus, the endophytic fungus associated with soybean roots, which is then subcultured using OSMAC approach in five different culture media. Analytical analysis of media ethylacetate extracts using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) was carried out. Furthermore, the obtained LC-MS data were statistically processed with MetaboAnalyst 4.0. Molecular docking studies were performed for the dereplicated metabolites against COVID-19 main protease (Mpro ). Metabolomic profiling revealed the presence of 18 compounds belonging to different chemical classes. Quinones, polyketides and isocoumarins were the most abundant classes. Multivariate analysis revealed that potato dextrose broth and modified potato dextrose broth are the optimal media for metabolites production. Molecular docking studies declared that the metabolites, Aspergillide B1 and 3a-Hydroxy-3, 5-dihydromonacolin L showed the highest binding energy scores towards COVID-19 main protease (Mpro ) (-9·473) and (-9·386), respectively, and they interact strongly with the catalytic dyad (His41 and Cys145) amino acid residues of Mpro . CONCLUSIONS: A combination of metabolomics and in-silico approaches have allowed a shorter route to search for anti-COVID-19 natural products in a shorter time. The dereplicated metabolites, aspergillide B1 and 3α-Hydroxy-3, 5-dihydromonacolin L were found to be potent anti-COVID-19 drug candidates in the molecular docking study. SIGNIFICANCE AND IMPACT OF THE STUDY: This study revealed that the endophytic fungus, A. terreus can be considered as a potential source of natural bioactive products. In addition to, the possibility of developing the metabolites, aspergillide B1 and 3α-Hydroxy-3, 5-dihydromonacolin L to be used as phytopharmaceuticals for the management of COVID-19.

[In silico Screening of Flavones and its Derivatives as Potential Inhibitors of Quorum-Sensing Regulator LasR of Pseudomonas aeruginosa].

Antibiotic resistance is a global problem nowadays and in 2017 the World Health Organization published the list of bacteria for which treatment are urgently needed, where Pseudomonas aeruginosa is of critical priority. Current therapies lack efficacy because this organism creates biofilms conferring increased resistance to antibiotics and host immune responses. The strategy is to "not kill, but disarm" the pathogen and resistance will be developed slowly. It has been shown that LasI/LasR system is the main component of the quorum sensing system in P. aeruginosa. LasR is activated by the interaction with its native autoinducer. A lot flavones and their derivatives are used as antibacterial drug compounds. The purpose is to search compounds that will inhibit LasR. This leads to the inhibition of the synthesis of virulence factors thus the bacteria will be vulnerable and not virulent. We performed virtual screening using AutoDock Vina, rDock, LeDock for obtaining consensus predictions. The results of virtual screening suggest benzamides which are synthetical derivatives of flavones as potential inhibitors of transcriptional regulator LasR. These are consistent with recently published experimental data, which demonstrate the high antibacterial activity of benzamides. The compounds interact with the ligand binding domain of LasR with higher binding affinity than with DNA binding domain. Among the selected compounds, by conformational analysis, it was found that there are compounds that bind to the same amino acids of ligand binding domain as the native autoinducer. This could indicate the possibility of competitive interaction of these compounds. A number of compounds that bind to other conservative amino acids ligand binding domain have also been discovered, which will be of interest for further study. Selected compounds meet the criteria necessary for their consideration as drugs and can serve as a basis for conducting further in vitro/in vivo experiments. It could be used for the development of modern anti-infective therapy based on the quorum sensing system of P. aeruginosa.