Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium that is present commonly in soil and water and is responsible for causing septic shock, pneumonia, urinary tract and gastrointestinal infections, etc. The multi-drug resistance (MDR) phenomenon has increased dramatically in past years and is now considered a major threat globally, so there is an urgent need to develop new strategies to overcome drug resistance by P. aeruginosa. In P. aeruginosa, a major factor of drug resistance is associated to the formation of biofilms by the LasR enzyme, which regulates quorum sensing and has been reported as a new therapeutic target for designing novel antibacterial molecules. In this study, virtual screening and molecular docking were performed against the ligand binding domain (LBD) of LasR by employing a pharmacophore hypothesis for the screening of 2373 FDA-approved compounds to filter top-scoring hit compounds. Six inhibitors out of 2373 compounds were found to have binding affinities close to that of known LasR inhibitors. The binding modes of these compounds to the binding site in LasR-LBD were analyzed to identify the key interactions that contribute to the inhibition of LasR activity. Then, 50 ns simulations of top hit compounds were performed to elucidate the stability of their binding conformations with the LasR-LBD. This study, thus concluded that sulfamerazine showed the highest binding affinity for the LasR-LBD binding pocket exhibiting strong inhibitory binding interactions during molecular dynamics (MD) simulation.
Heterocyclic nuclei have shown a wide variety of biological activities, highlighting their importance in drug discovery. Derivatives of 2,4-subsituted thiazolidine have a structural similarity with the substrates of tyrosinase enzymes. Hence, they can be used as an inhibitor to compete against tyrosine in the biosynthesis of melanin. This study is focused on design, synthesis, biological activities, and in silico studies of thiazolidine derivatives substituted at positions 2 and 4. The synthesized compounds were evaluated to determine the antioxidant activity and tyrosine inhibitory potential using mushroom tyrosinase. The most potent tyrosinase enzyme inhibitor was compound 3c having IC50 value 16.5 ± 0.37 µM, whereas compound 3d showed maximum antioxidant activity in a DPPH free radical scavenging assay (IC50 = 18.17 µg/mL). Molecular docking studies were conducted using mushroom tyrosinase (PDB ID: 2Y9X) to analyze binding affinities and binding interactions of the protein–ligand complex. Docking results indicated that hydrogen bonds and hydrophobic interactions were mainly involved in the ligand and protein complex. The highest binding affinity was found to be −8.4 Kcal/mol. These results suggest that thiazolidine-4-carboxamide derivatives could serve as lead molecules for development of novel potential tyrosinase inhibitors.
Plants thrive in a complex environment comprising of various biotic and abiotic agents. Like all biological systems, these agents tend to interact with the plant body. Microorganisms form a major portion of the ecosystem and have been found to inoculate or infect members of all the kingdoms. Plants and microbes have developed molecular mechanisms to interact with one another and attain the maximum benefi t from the interactions. This mutualistic relationship provides benefi t not only to the microbes but also to the plants. Based upon this complex molecular interplay, a number of mechanisms have been studied and are currently being employed for the agricultural, environmental, and health benefi ts. The principles of biofertilization and bioremediation utilize the plant-microbe interactions for the survival of the two players along with contributing to the food chain and the ecosystem. Similarly, the secondary metabolites obtained from these organisms contribute to human medical and agricultural welfare. These processes are regulated by a variety of biological, physical, chemical, and environmental factors, the study of which can be helpful in exploiting better outcomes from the interaction. The advent of modern techniques has helped in deciphering the role of various molecular players of the plant-microbe interactions. Moreover, they can be employed for regulating the plant-microbe interaction for improved effi ciency. The current chapter discusses the molecular mechanisms involved in the plant-microbe interactions exhibited in biofertilization, bioremediation, biocontrol, and induced systemic resistance. Afterwards, the factors affecting the molecular machinery involved in these pathways have been discussed. Toward the end, a brief introduction of the genetic 2 manipulative techniques and their applications in the plant-microbe interactions has been presented.
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