In silico approach for potential antimicrobial agents through antiviral, molecular docking, molecular dynamics, pharmacokinetic and bioactivity predictions of galactopyranoside derivatives

Abstract

Carbohydrates derivatives played an important and vital role in a large part to design new potential drug against various pathogens, in medicinal chemistry. Also, monosaccharide derivatives are very useful in biological chemistry because monosaccharide binding agents were shown to possess antiviral, antibacterial, and antifungal activity towards HIV, Dengue coronaviruses, and many members of the family Enterobacteriaceae, including strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Shigella flexneri, and Enterobacter aerogenes. The present study was therefore interesting in identifying the binding affinity of a series of monosaccharides previously synthesized through their physicochemical and pharmacokinetic properties. These monosaccharides are derivatives of methyl-β-D-galactopyranoside (MGP) coupled to the protein deacetoxycephalosporin C synthase (DAOCS) of Streptomyces clavuligerus (1RXF). Molecular docking study against DAOCS proteins (PDB ID: 1RXF) was performed assess the antimicrobial activities of these derivatives along with antiviral prediction. The results of molecular docking studies showed that derivatives 8 and 10 both presented the highest score (-7.2 kcal/mol), reflecting their good binding affinity toward the active pocket of the pathogen S. clavuligerus (1RXF). They are found to be potent antimicrobial agents. These findings were further validated in dynamics (200 ns) milieu and intermolecular stability was evaluated via highly acceptable Molecular Mechanics Poisson-Boltzmann Surface Area (MMPB)/Molecular Mechanics/Generalized Born Surface Area (GBSA) binding free energies estimation methods. The dynamics of the complexes are highly stable with the strengthening of docked interactions as highlighted by MMPB/GBSA method (net binding energy < −40 kcal/mol). Density functional theory (DFT) calculations were carried out on the derivatives of MGP in order to determine the partial atomic charges, electronic energies, enthalpies, entropies and polarizability, at the B3LYP/3-21G level. The in silico ADMET prediction carried out provided access to the bioactivity and toxicity parameters which established that most of the different ligands designed are safe to use as drugs. This in silico study provided an overall view of the possible pharmacological and therapeutic profile of MGP derivatives. It therefore, paved the way for the discovery of promising next-generation drugs against pathogenic microbes.