Integrated molecular docking, molecular dynamics, and MM/PBSA studies of Azadirachta indica phytochemicals as potential DNA gyrase inhibitors against methicillin-resistant Staphylococcus aureus (MRSA)

Title : Integrated molecular docking, molecular dynamics, and MM/PBSA studies of Azadirachta indica phytochemicals as potential DNA gyrase inhibitors against methicillin-resistant Staphylococcus aureus (MRSA)

Abstract:

Methicillin-resistant Staphylococcus aureus (MRSA) remains a global health concern due to increasing resistance to conventional antibiotics, necessitating the search for novel antimicrobial agents. This study applied a structure-based drug design approach to investigate the inhibitory potential of phytochemicals from Azadirachta indica against MRSA DNA gyrase, a validated antibacterial target essential for DNA replication. A total of 169 compounds from A. indica, along with two reference antibiotics (amoxicillin and ciprofloxacin), were retrieved from the PubChem database and optimized using Density Functional Theory (B3LYP/6-31G*) in Spartan 14. Preliminary in silico screening, including ADMET profiling, drug-likeness evaluation, oral bioavailability analysis, and molecular interaction studies, identified ten promising compounds for docking against the DNA gyrase (PDB ID: 1KZN) using PyRx software. The docking result identified C31 (-8.6 kcal/mol) and C111 (-7.3 kcal/mol) as probable inhibitors of the drug target, comparable to ciprofloxacin (-8.0 kcal/mol) and amoxicillin (-7.5 kcal/mol). Both formed key hydrogen bonding, hydrophobic and electrostatic interactions with catalytic residues such as Thr165, Asn46, Ile78, Ala47, and Ile90, similar to the co-crystallized ligand clorobiocin. The 100 ns molecular dynamics simulations further validated the structural stability of the protein-ligand complexes, with both leads showing lower RMSD values (<0.25 nm) as compared to the standard drug. The MM/PBSA analysis identified C111 as the most favourable inhibitor, with a ΔG_total of -13.06 kcal/mol, driven by strong van der Waals and electrostatic contributions. Overall, the identified lead compounds, C111 and C31, show promising inhibitory potential, favourable pharmacokinetics, and stable interactions with MRSA DNA gyrase, necessitating further in vitro and in vivo validation as potential anti-MRSA candidates.

Key words: Azadirachta indica, DNA gyrase, Methicinin Resistant Staphylococcus aureus, ligands, Molecular docking, Molecular dynamics simulation

Biography:

Ibrahim Olaide Adedotun is a research-driven chemist specializing in computational drug discovery, medicinal chemistry, and structure-based drug design. He holds an M.Sc. in Chemistry from the University of Ibadan and a B.Tech. in Pure and Applied Chemistry from LAUTECH, Nigeria. His research focuses on molecular docking, molecular dynamics simulation, ADMET profiling, and natural product-based drug discovery for cancer, malaria, and infectious diseases. He has authored over 30 scholarly publications and has presented at several national and international conferences. He is passionate about translating chemical research into therapeutic solutions for African health challenges.