RESUMEN
With the escalating threat of antimicrobial resistance (AMR), discovering novel therapeutic agents against resistant pathogens like Staphylococcus aureus is crucial. This study explores phytochemicals from Syzygium cumini for their potential efficacy against AMR S. aureus infections, elucidating their mechanisms through in silico methods. We investigated 83 compounds from S. cumini, sourced from PubMed, using rigorous docking analysis against the ATP binding domain AgrC of S. aureus with AMdock with Autodock Vina v1.5.2. Drug-likeness predictions were assessed using SwissADME v2023 and Pass online v2.0. Molecular dynamics (MD) simulations identified promising compounds, focusing on stability and interaction dynamics. Beta-Glucogallin (BEG) and Dihydro Dehydro Coniferyl alcohol (DIH) emerged as significant hits. MD simulations with GROMACS v2020.6 revealed stable BEG and DIH complexes with AgrC, forming six hydrogen bonds with six key amino acids (Arg-303, Asp-338, Glu-342, Glu-384, Lys-389, Gly-396), indicating strong and stable bonding. The binding affinities for DIH and BEG are -73.474 ± 11.104 kJ/mol and -6.319 ± 18.823 kJ/mol with 4BXI, respectively. Our findings highlight BEG and DIH as promising candidates against AMR S. aureus infections, showing favourable binding affinities and stable interactions with AgrC. This study underscores the importance of natural products in combating AMR and demonstrates the utility of computational methodologies in drug discovery. Further experimental validation is warranted to fully exploit these phytochemicals' therapeutic potential.
RESUMEN
Incidences of Methicillin-Resistant Staphylococcus aureus and Multi-Drug Resistant Pseudomonas aeruginosa causing skin and soft tissue infections are becoming more prevalent due to repeated mutations and changes in the environment. Coriandrum sativum, a well-known Indian herbal medicinal plant, is shown to have antioxidant, antibacterial, and anti-inflammatory activity. This comparative study focuses on the molecular docking (PyRx v0.9.8) of ligand binding domains of WbpE Aminotransferase involved in O-antigen assembly in Pseudomonas aeruginosa (3NU7) and Beta-Lactamase found in Staphylococcus aureus (1BLC) with selected phytocompounds of Coriandrum sativum along with a known binder and a clinical reference drug. This was followed by molecular dynamics simulation studies (GROMACS v2019.4) for the docked complexes (with Geranyl acetate) with the best binding affinities (-23.4304 kJ/mol with Beta-Lactamase and -28.4512 kJ/mol with WbpE Aminotransferase) and maximum hydrogen bonds. Molecular dynamics simulation studies for both the proteins demonstrated that the complex with Geranyl acetate showed stability comparable to the complex with reference drug observed via Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and H-bond analyses. Changes in the secondary structural elements indicated that Geranyl acetate could possibly cause improper functioning of WbpE Aminotransferase leading to disrupted cell wall formation. Further, MM/PBSA analyses showed significant binding affinity of Geranyl acetate with WbpE Aminotransferase and Beta-Lactamase. This study aims to provide rationale for further studies of Coriandrum sativum as an antimicrobial, and to contextualise the results in the current scenario of growing antimicrobial resistance. HIGHLIGHTSPhytoconstituents present in Coriandrum sativum show significant binding affinity to the proteins in Pseudomonas aeruginosa and Staphylococcus aureus.Geranyl acetate exhibited the highest binding affinity with WbpE Aminotransferase involved in O-antigen assembly in Pseudomonas aeruginosa (PDB ID:3NU7) and Beta-Lactamase found in Staphylococcus aureus (PDB ID: 1BLC)Molecular dynamics simulation analyses show that the phytoconstituent, Geranyl acetate has an effect similar to the clinical reference drug, thus exhibiting potential antibacterial activity.Communicated by Ramaswamy H. Sarma.