Molecular Insights into 14-Membered Macrolides Using the MM-PBSA Method

Abstract

Erythromycin A and roxithromycin are clinically important macrolide antibiotics that selectively act on the bacterial 50S large ribosomal subunit to inhibit bacteria's protein elongation process by blocking the exit tunnel for the nascent peptide away from ribosome. The detailed molecular mechanism of macrolide binding is yet to be elucidated as it is currently known to the most general idea only. In this study, molecular dynamics (MD) simulation was employed to study their interaction at the molecular level, and the binding free energies for both systems were calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The calculated binding free energies for both systems were slightly overestimated compared to the experimental values, but individual energy terms enabled better understanding in the binding for both systems. Decomposition of results into residue basis was able to show the contribution of each residue at the binding pocket toward the binding affinity of macrolides and hence identified several key interacting residues that were in agreement with previous experimental and computational data. Results also indicated the contributions from van der Waals are more important and significant than electrostatic contribution in the binding of macrolides to the binding pocket. The findings from this study are expected to contribute to the understanding of a detailed mechanism of action in a quantitative matter and thus assisting in the development of a safer macrolide antibiotic.

Mixing Atomistic and Coarse Grain Solvation Models for MD Simulations: Let WT4 Handle the Bulk

“…56 Since the amount of atomistic water depends on the exposed surface of the solute, globular systems are more convenient than membranes. In highly solvated systems such as a bacterial rybozome, 66 containing about 300 000 water molecules and ions, our approach would allow for a reduction of about 75% in system size. Other mixed approaches, such as the use of a reaction field after a given distance from the solute, 67 may provide a similar gain.…”

Enantioselective drug–protein interaction between mexiletine and plasma protein

“…examined the energy contributions and roles of amino acid residues of HSA in flavone binding using MD simulations [10] and Yam et al . studied the interaction of 14‐membered macrolides with a bacterial 50S large ribosomal subunit [11] …”

Antimicrobial Activity of Galangin and Its Effects on Murein Hydrolases of Vancomycin-Intermediate Staphylococcus aureus (VISA) Strain Mu50

“…The mechanisms by which antimicrobial agents inhibit bacterial growth are numerous and diverse. For example, sulfonamides inhibit bacterial growth by inhibiting dihydrofolate synthetase, macrolides inhibit bacterial growth by reversibly binding to the P site on the 50S subunit of the bacterial ribosome, and aminoglycosides inhibit bacterial growth by disturbing peptide elongation at the 30S ribosomal subunit [26,27]. Additionally, to explore the possible reasons for galangin to inhibit Mu50 growth, we observed morphological changes using TEM.…”