Molecular Dynamics Simulation Studies for the Antibacterial Activity of Bioactive Compound from Syzygium cumini against AMR Staphylococcus aureus
Authors: P Shravani , N Bhavyashree , M. S Vaishnavi , Sabat Sasmita 
Published: June 2024

Background:
To understand the effectiveness of identified bioactive compounds derived from Syzygium cumini as antibacterial agents against Staphylococcus aureus infections was studied. Antimicrobial resistance (AMR) has put many modern treatments aside and proved ineffective over many human infections. The misuse and inappropriate overuse of antimicrobials in human has developed drug-resistant pathogens, called as “superbugs”. Currently, World is facing a rise in the crisis regarding the strategic information and innovation with a novel breakthrough on demand with an efficient, safe and alternative drug to check severe attack of AMR. Herbal medicines are now been pipelined with substantial understanding and trials in complete treatment for many AMR infections. This study is an innovative approach shows a constant stability by directly inhibiting the protein involved in cell wall synthesis of the pathogen with the ligand selected on interaction.

Objectives:
i) Elucidating the bidirectional approach of bioactive compounds identified from Syzygium cumini as an alternative drug to control infection caused due to AMR Staphylococcus aureus.
ii) Molecular dynamics simulation analysis to prove its significance in understanding the mechanism of penicillin binding protein 2a responsible in cell wall synthesis in AMR Staphylococcus aureus being inhibited by the bioactive compounds more effectively than FDA approved drug.
iii) The bioactive compounds selected were studied for antibacterial and anti-inflammatory activities.

Methods:
Molecular docking study was performed using AMdock v1.5.2 with the PBP2a from Staphylococcus aureus. For these compounds SwissADME v2023 and Pass online v2.0 was used to understand the drug-likeness prophecies. MD simulations identified Beta-Glucogallin (BEG) and Dihydro Dehydro Coniferyl alcohol (DIH) as hit compounds. Using GROMACS v2020.6 BEG & DIH, identified for molecular dynamics simulation studies; indicated maximum hydrogen bonds. All the results RMSD, RMSF, SASA, RG, H bonding and MMPBSA were compared and analysed with FDA approved drug. The phytocompounds present in Syzygium cumini were retrieved from the PubMed database.

Results:
Binding affinities for DIH and BEG; -55.202 +/-20.494 and 27.972+/-16.329 with 1MWU respectively. The RMSD (1MWU-APO, 1MWU-MET, 1MWU-BEG and 1MWU-DIH complex proteins were 0.860 +/- 0.04 nm, 0.80 +/- 0.08 nm, 0.56 +/- 0.07 nm, 0.51 +/- 0.10 nm respectively). RMSF (1MWU-APO, 1MWU-MET, 1MWU-BEG and 1MWU-DIH complex proteins were 0.27 +/- 0.14 nm, 0.20 +/- 0.09 nm, 0.29 +/- 0.16 nm, 0.29 +/- 0.14 nm respectively). RG (1MWU-APO, 1MWU-MET, 1MWU-BEG and 1MWU-DIH complex proteins were 3.47 +/- 0.09 nm, 3.45 +/- 0.05, 3.66 +/- 0.04 nm, 3.63 +/- 0.06 nm respectively). SASA (1MWU-APO, 1MWU-MET, 1MWU-BEG and 1MWU-DIH complex proteins were 312.26 +/- 7.43 nm, 319.68 +/- 4.46, 321.16 +/- 4.85 nm, 338.4 +/- 4.05 nm respectively.

Conclusions:
The computational analysis utilised molecular docking and molecular dynamics simulations to evaluate interactions between S. aureus ATP binding domain AgrC, Penicillin binding protein 2a (PBP2a) and phytochemical compounds from Syzygium cumini. Among the compounds analysed, Beta-Glucogallin (BEG) and Dihydro Dehydro Coniferyl alcohol (DIH) exhibited stable binding and interactions, demonstrating potential as antimicrobial agents. PASS software analysis further supported their antibacterial and anti-inflammatory activities, indicating the need for subsequent in vitro and in vivo validation studies. These compounds show promise as leads for drug development efforts to address antimicrobial resistance.