Binding affinities and molecular dynamics simulations of selected approved drugs and Mucuna pruriens phytoconstituents with Escherichia coli Shiga toxin

Shiga toxin (Stx)–producing Escherichia coli (STEC), also known as “verocytotoxin- producing E. coli” is a major food and waterborne pathogen of zoonotic origin. STEC infection is involved in several life-threatening disease conditions that includes diarrhea, hemorrhagic colitis, and hemolytic-uremic syndrome.  We determined the binding affinities of selected approved drugs and Mucuna pruriens phytoconstituents to shiga toxin and ricin receptors (a toxin similar in structure to shiga toxin) by molecular docking simulations. The 3D crystal structures of Stx1, Stx2 and ricin receptor were obtained from the protein data bank. The receptors were prepared using PyMol 1.1eval, Chimera 1.10.1 and AutoDock tools vs 1.5.6. The 3D structures of selected approved drugs and Mucuna pruriens phytoconstituents were obtained from ZINC and PubChem databases. They were prepared for molecular docking simulations using AutoDock tools vs 1.5.6. Docking protocols were validated by reproducing the PDB crystal structures in silico. Molecular docking simulations were executed with a virtual screening script using AutoDockVina 1.1.2 on a Linux platform. Molecular dynamics simulations of two front runner compounds with the reference ligand and protein were done in 1500 ps.  Morphine, Butorphanol and riboflavin (phytoconstituent of Mucuna pruriens) had binding affinities of -6.6±0.0,-6.4±0.1 and -6.2±0.1 kcal/mol respectively as while the reference ligand, 3-(pyridine-1-ium-1-yl)propane-1-sulfonate had binding affinity of -4.5±0.0kcal/mol. Higher stability were demonstrated by morphine and butorphanol in the molecular dynamics simulations. Morphine, butorphanol and riboflavin are predicted as possible shiga toxin antidotes.