Computational Study on Potentially Active Antibacterial Compounds in Secondary Metabolites of Extremophilic Microorganisms

The density functional theory (DFT) method ωB97XD/6-311+G(2d, p) was employed to perform systematic theoretical calculations and comparative analyses on the geometric structures, spectroscopic properties, frontier molecular orbitals, and molecular electrostatic potentials of potential antibacterial compounds derived from 16-membered lactone ring-containing secondary metabolites of extremophiles, as well as midecamycin. The reactivity indices of these compounds were further investigated within the framework of conceptual DFT. Additionally, drug-likeness was evaluated using two independent pharmacokinetic prediction platforms, and molecular docking simulations were conducted to assess their binding affinities. The results indicate that the carboxyl hydrogen, hydroxyl hydrogen, and carbonyl oxygen atoms in these molecules exhibit relatively high reactivity. Compound 3 displays relatively high chemical reactivity, whereas compounds 6 and 9 demonstrate superior chemical stability combined with significant reactivity. Pharmacokinetic predictions reveal poor Caco-2 permeability for compounds 8 and 9, low therapeutic indices for compounds 2 and 3, and the highest metabolic stability in human liver microsomes for compound 7. Overall, compound 1 exhibits the highest structural and physicochemical similarity to midecamycin. Compound 1 was evaluated for molecular docking with the 50S ribosomal subunit from Streptomyces bacteria; the molecular docking results confirm its distinct binding affinity, despite a slightly higher binding energy. The molecular dynamics simulation results indicate that complex 1 exhibits a Gibbs free energy of -30.76 kJ/mol, further supporting its structural stability.