Inhibitors of Heptosyltransferase I to prevent heptose transfer against antibiotic resistance of E. coli: Energetics and stability analysis by DFT and molecular dynamics

Abstract

Heptosyltransferase I (HEP I) belongs to the broad family of glycosyltransferase-B (GT-B) enzymes, which transfers heptose sugar necessary for the lipopolysaccharide (LPS) synthesis. LPS is a significant component of the external cell membrane of Gram-negative bacteria, e.g., Escherichia coli. Interruption of heptose sugar addition during LPS biosynthesis greatly reduces bacterial infections and antibiotic resistance. Thus, inhibition of HEP I is indispensable to counteract this problem. Here, we have performed virtual screening employing structure-based pharmacophore, docking, pharmacokinetics, and electronic descriptors to identify four important hit molecules from a pool of ∼108 million bioactive molecules existing in ZINC, PubChem, and CHEMBL databases against HEP I. Pharmacokinetics and all electronic descriptors describing the bioavailability of the selected hits fall within the permissible limits. Further, molecular dynamics simulations of the shortlisted hits along with a reference molecule discern the conformational stability of the bound complexes, characterized by RMSD, RMSF, Rg, SASA, and PCA. The large negative MM-PBSA-based binding free energy validates the initial screening results and hence the inhibitory potential of the hits. The study suggests that the best three candidates, hit 1 (CHEMBL1438912), hit 3 (CHEMBL13895), and hit 4 (CHEMBL320880), can be very promising to retard the heptose sugar transfer and eradicate the antibiotic resistance of E. coli, providing molecular insights into the inhibition of HEP I. This may facilitate further in-vitro studies of the best hits and targeted antibacterial drug development.