In Silico Study of Compounds from Four Tropical Medicinal Plants as Allosteric Gyrase Inhibitor of Multidrug-Resistant E. coli

Abstract

The enormity and economic implications due to Escherichia coli infections and its resistance to valued antibiotics including fluoroquinolones in poultry production demand urgent alternative drugs from medicinal plants with a novel mechanism of action. Fifteen identified compounds from the four tropical medicinal plants, Petiveria alliacea, Solanum erianthum, Alternanthera brasiliana, and Hoslundia opposita, were subjected to molecular docking against the DNA gyrase of E. coli using Schrödinger software. The 3-dimensional (3D) x-ray chrystallographic structure of DNA gyrase A of E. coli with PDB ID-8QQI was retrieved in a co-crystallized form with isoquinoline-5-sulfonamide from protein data bank (PDB). The ligands were docked into its allosteric site occupied by the co-crystallized ligand. Post docking analyses were carried out through molecular mechanics/generalized born surface area (MM/GBSA), pharmacophore modelling and docking validation. Absorption, distribution, metabolism, excretion and toxicity (ADMET) of the ligands were predicted with appropriate online servers. The docking scores (kcal/mol) revealed gallic acid (-8.37), chlorogenic acid (-7.97), catechin (-7.20) and caffeic acid (-7.02) to be best among others, and also better than that of the reference drug isoquinoline-5-sulfonamide (-3.54). Nevertheless, the co-crystallized ligand recorded higher ΔGbind value (-71.93 kcal/mol) than the hit compounds (-37.50, -36.47, -52.77 and -29.87 kcal/mol). Gallic acid, chlorogenic acid, catechin, and caffeic acid were deemed drug-like following their docking scores, favourable predicted pharmacokinetic, physicochemical and ADMET properties. They are thus suggested for further studies ranging from in vivo to hits optimization in order to validate the results from the present study.