In silico Screening and Docking of Potential Lead Compounds and Designed Ligands Against Acinetobacter baumannii aminoglycoside acetyltransferase AAC(6’)-Ih and Peptidyl-tRNA Hydrolase (AbPth)

Abstract

Acinetobacter baumannii is a nosocomial pathogen that has exhibited multidrug resistance. Potential lead compounds with the ability to bind to the respective active sites of aminoglycoside acetyltransferase AAC(6’)-Ih and Peptidyl-tRNA hydrolase (Pth) and interfere with bacterial growth were constructed and screened in silico. A total of 6,699 compounds from the Traditional Chinese Medicine Systems Pharmacology Database were docked to the 3-D models of aminoglycoside acetyltransferase AAC(6’)-Ih and Pth. The top binders from the TCMSP compounds for AAC(6’)-Ih were MOL1810, MOL3664, MOL000450, and MOL003199 with binding energies of -12.8, -11.1 kcal/mol, -11.0, and -11 kcal/mol, respectively. The top binders to A. baumanii Pth were MOL004675, MOL004805, MOL000743, and MOL010194 with binding energies -7.9, -7.9, -7.8, and -7.8 kcal/mol, respectively. Selected TCMSP compounds with high binding affinities of at least -9 kcal/mol were virtually screened and ranked based on Lipinski’s rules. Using these TCMSP parent molecules, 10 ligands were designed for each enzyme. Four ligands had a binding energy of ΔG = -8 kcal/mol for aminoglycoside acetyltransferase AAC(6’)-Ih. D743x4675 had the lowest binding energy of -7.7 kcal/mol for Pth. For AAC(6’)-Ih, D1810x3649-1 and D1810x3649-2 had the lowest binding energies of -11.1 and -10.8 kcal/mol respectively. The designed ligands and TCMSP molecules show potential to be good drug lead candidates for treating Acinetobacter baumannii infections.