In silico screening and design of N-substituted 7-piperazin-1-ylfluoroquinolone-derived DNA gyrase inhibitor antibiotics

Abstract

As multidrug-resistant pathogens have increasingly become a serious public health problem, especially in the last decade, the design of new active agents against resistant organisms is of great importance.

The design of new pharmacologically active molecules against an enzyme can be done by virtual screening, based either on the ligand or on the structure of the target.

Docking is the "structure based" method used to measure the affinity of ligands for the DNA Gyrase protein, it allows to generate the different poses, their positions, orientations and conformations in the active site.

The predictions provided by virtual screening allow to propose a good strategy for the development of a good pharmacophore, it can thus constitute an adequate support to validate or reject a hypothesis.

The protein data base used in our study is 2XCT: The 3.35A° paired structure of the S. aureus Gyrase complex with ciprofloxacin and DNA, this pdb was chosen according to the criteria mentioned below and was downloaded from the protein data base.

According to the first part of our results, the molecules that contain nitrogen rings in position 7 are the most active, most of the marketed drugs take this basic structure.

The 7-piperazin-1-ylfluoroquinolone series is not fully exploited, especially the N-acylated and N-chloroalkylated derivatives.

In this study, we performed a docking test on a series of molecules selected according to their structures close to the reference inhibitors and which are likely to interact with DNA gyrase in-silico.