Molecular Docking and Redesign of Traditional Chinese Medicine Compounds Against VanA and VanX of Vancomycin-resistant Enterococcus faecium

Abstract

Enterococci are gram-positive bacterial which have been linked to serious and life-threatening infections in humans, despite their inherent presence in the environment and in human and animal intestinal microbiota. Vancomycin-resistant enterococci are rapidly becoming a cause of concern due to antibiotic misuse. Van A and Van X are enzymes that confer vancomycin type I resistance. VanA catalyzes ester bond formation between D-Ala and various D-hydroxy acids, and VanX cleaves D-Ala-D-Ala dipeptides into individual D-Ala residues. These result in decreased vancomycin affinity and the substitution of native peptidoglycan precursor with the resistant variant. This study aims to identify top hit compounds and to design novel ligands based on Traditional Chinese Medicine compounds that can bind with high affinity in silico to Enterococcus faecium Van A and VanX active sites. A total of 6,699 pre-screened molecules from the Traditional Chinese Medicines Systems Pharmacology (TCMSP) database were docked to the active sites of the enzymes. The top 20 ligands for each enzyme were chosen based on binding free energy (∆G). The top-binding molecules for each enzyme were also evaluated based on their physicochemical properties and compliance with Lipinski’s rule of five. Binding affinities were further improved through ligand redesign, wherein top-scoring parent ligands were modified by comparing, trimming, and joining ligands together through fragment joining or merging. The top three redesigned molecules for Van A and VanX were selected based on their binding free energy. MOL007866 (P1_A), MOL009074 (P2_A) and MOL012715 (P3_A) are the top TCMSP molecules, while R1_A, R2_A, R3_A are the top redesigned ligands for VanA. All redesigned molecules docked with VanA had binding energies less than -12.0kcal/mol, high solubility and satisfied Lipinski’s rule of five. MOL011124 (P1_B), MOL011100 (P2_B), and MOL008243 (P3_B) are the top TCMSP molecules, while R1_B, R2_B, and R3_B are the top redesigned ligands for VanX. Redesigned molecules docked with VanX had binding energies less than -9.2kcal/mol, low to moderate solubility, and complied with Lipinski’s rule of five except for their molecular weights. The identified top-binding TCMSP molecules and redesigned ligands may be used in succeeding drug design studies, and subjected to additional docking and virtual screening to increase binding affinities and improved their bioavailability scores.