Elucidating the Potential of Isatin Derivatives as Antimicrobial Agents: DFT Calculations and MD Simulations

In response to the development of antibiotics, various sources, including medicinal plants and synthetic chemicals, have been considered. Herein, the antimicrobial activities of isatin derivatives (3a, 3b, 3c and 3d) against Escherichia coli (E. coli.) and Staphylococcus aureus (S. aureus.) proteins were elucidated using DFT calculations and MD simulations. In an attempt to mimic the biological environment, the role of water in the studied isatin derivatives was evaluated. From the emerged outcomes, the vibrational frequencies illustrated the in-plane and out-of-plane bending vibrations associated with the CC and CH groups in the studied isatin derivatives. Upon frontier molecular orbitals (FMOs) analysis, isatin derivative 3c exhibited high chemical reactivity, with an E gap value of 2.880 eV, followed by 3d, 3a and 3b analogs. Further, molecular electrostatic potential (MEP) maps, noncovalent interaction (NCI) index and natural bond orbital (NBO) analyses were performed for the studied isatin derivatives. In accordance with DFT calculations, the chemical reactivity of the studied isatin derivatives was highlighted, where isatin derivative 3c was the most favorable. Turning to molecular docking analysis, isatin derivative 3c demonstrated the lowest docking score against S. aureus. with a value of −8.8 kcal/mol. Meanwhile, all studied isatin derivatives manifested convergent docking values against E. coli. From MD simulations over 200 ns, isatin derivative 3c illustrated the lowest MM-GBSA binding energy with a value of −35.6 kcal/mol[Formula: see text]in complex with S. aureus. Additionally, isatin derivatives 3c and 3d demonstrated promising MM-GBSA binding energies with values of −18.6 and −24.3 kcal/mol in complex with E. coli., respectively. Upon the MD simulations, the promising binding interactions of isatin derivatives, particularly 3c, within active sites of S. aureus. and E. coli. proteins were affirmed. The current emerging DFT and MD findings provided in-depth insights into the potential antimicrobial activity of the investigated isatin derivatives toward S. aureus. and E. coli. proteins.