In Silico Screening, Docking, and Redesigning of Traditional Chinese Medicinal Compounds Against Clostridioides difficite TcdA and TcdB Glucosyltransferase Domains

Abstract

Clostridioides difficile is the leading cause of healthcare-associated infections in the United States and is currently an urgent threat to public health worldwide. The intestinal pathogen is increasing in prevalence and severity due to its frequent association with antibiotic use. The glucosyltransferase domains (GTD) of TcdA abd TcdB are promising drug design targets since both are primary determinants of C. difficile disease pathogenesis. In this study, molecular docking was performed utilizing 6,699 curated molecules from the Traditional Chinese Medicines Systems Pharmacology (TCMSP) database that were docked against the binding sites of TcdA-GTD and TcdB-GTD. The ligands with the highest binding affinities to each of TcdA and TcdB were selected and ranked, and their physiochemical properties were determined. 13 out of 20 TcdA ligands and 7 out of the 20 TcdB ligands satisfied Lipinski’s role of five parameters. These ligands were further redesigned to decrease binding energy and improve compliance with Lipinski's Ro5. The top three redesigned ligands for TcdA were MOL008014_and_MOL012692_R2 (R1a), MOL008014_and_MOL012692_R3 (R1b), and MOL004015_and_MOL012692_R2 (R1c), with binding energies of -11.6, -11.0, and -10.9 kcal/mol, respectively and were calculated to be soluble using logS solubility criteria. For TcdB, the top three redesigned ligands were MOL11111x004676 (R2a), MOL11110x009754 (R2b), and MOL004676x013370 (R2c), also soluble with binding energies of -13.56, -12.22, and -12.04 kcal/mol, respectively. These top-binding ligands are recommended for post-docking modification refinements and redocking for drug lead improvement. Results from this study can potentially be utilized for future studies in novel drug discovery for the treatment of C-difficile.