In silico design based on quantum chemical, molecular docking studies and ADMET predictions of ciprofloxacin derivatives as novel potential antibacterial and antimycrobacterium agents

Abstract

Drug designing and development is an important area of research for pharmaceutical companies and chemical scientists. In this paper, we report the prediction of new ciprofloxacin derivatives by quantum chemical, molecular docking studies and pharmacokinetic properties. Theoretical studies were performed by geometry optimization computation using B3LYP level at 6-311 G (d,p) basis set. The absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters were predicted and the result show that all compounds have a great ADMET profile. To study the antibacterial, anti-Mycobacterium tuberculosis activities, ciprofloxacin and its derivatives were interacted with the proteins: Thymidylate Kinase (PDB: 4QGG), Biotin carboxylase (PDB: 3JZF) and β-lactamase BlaC (PDB: 3N7W). The results of the docking studies indicate that one pharmacophore designed presents a great inhibition behavior against gram-positive organism (4QGG) and significant interactions observed between the compound and ARG48, GLN101, ARG105 and GLU37 residues of 4QGG. Also, another derivative designed present the best inhibition against gram-negative organism (3JZF) several interactions were noticed between the compound and GLY165, ILE287, LEU278, HIS236, HIS209, MET169 and LYS159 residues of (3JZF). As well as, one designed candidate is good inhibitors for β-lactamase (3N7W) multiple no bonded interactions were observed between the compound and SER84, ILE117, ASN186, LYS87, ARG187, ASN186 and THR251 residues of(3N7W). Molecular dynamics (MD) simulation study was also performed for 100 ns to confirm the stability behaviour of the main protein and inhibitor complexes. The MD simulation study validated the stability of three compounds in the protein binding pocket as potent binders. Natural bonding orbital analysis, reactivity indices and molecular electrostatic potential were carried out. The research finding of this study can be helpful to design a new potent antibacterial, antimycrobacterium candidate’s drugs that will serve as the basis for future in vitro and in vivo research. Communicated by Ramaswamy H. Sarma