Identification of potential DNA gyrase inhibitors: virtual screening, extra-precision docking and molecular dynamics simulation study

Abstract

DNA gyrase brings negative supercoils into DNA and loosens up certain positive supercoils that collect during replication and transcription and is a notable antibacterial target. To fight against the menace of antibiotic-resistant bacterial infections, we have employed various computational tools like high throughput virtual screening (HTVS), standard precision (SP) docking, extra precision (XP) docking, and molecular dynamics (MD) simulation studies to identify some potential DNA gyrase inhibitors. A focused library of 5968 anti-bacterial compounds was screened using the HTVS docking protocol of the glide module of Maestro. The top 200 docked compounds were further filtered using SP and XP docking protocols, and their free binding energies were calculated using MM-GBSA studies. The binding and stability of the top two compounds which showed better docking scores than the co-crystallized ligand (Clorobiocin) of DNA gyrase (PDB ID: 1KZN) were further probed by MD simulation of 100 ns using GROMACS. MD simulation study suggested that the compounds AM1 and AM5 form a stable complex with DNA gyrase with a good number of hydrogen bonds. XP docking study showed that interaction with the crucial amino acids for compounds AM1 and AM5 was like the co-crystallized ligand. These compounds were also predicted to be drug-like molecules with good water solubility and excellent absorption profiles. Based on the above studies, herein we report compounds AM1 (1R,3S)-1-(2-((3-(ammoniomethyl)phenyl)amino)-2-oxoethyl)-3-carbamoylpiperidin-1-ium and AM5 (1'S,2 s,4R)-4-ammonio-6-ethyl-1'-methylspiro[chromane-2,4'-piperidin]-1'-ium as potential DNA gyrase inhibitors which can be further developed as a potential lead against the menace of antibiotic resistance.