Combinatorially-generated library of 6-fluoroquinolone analogs as potential novel antitubercular agents: a chemometric and molecular modeling assessment

Abstract

The virtual combinatorial chemistry approach as a methodology for generating chemical libraries of structurally-similar analogs in a virtual environment was employed for building a general mixed virtual combinatorial library with a total of 53.871 6-FQ structural analogs, introducing the real synthetic pathways of three well known 6-FQ inhibitors. The druggability properties of the generated combinatorial 6-FQs were assessed using an in-house developed drug-likeness filter integrating the Lipinski/Veber rule-sets. The compounds recognized as drug-like were used as an external set for prediction of the biological activity values using a neural-networks (NN) model based on an experimentally-determined set of active 6-FQs. Furthermore, a subset of compounds was extracted from the pool of drug-like 6-FQs, with predicted biological activity, and subsequently used in virtual screening (VS) campaign combining pharmacophore modeling and molecular docking studies. This complex scheme, a powerful combination of chemometric and molecular modeling approaches provided novel QSAR guidelines that could aid in the further lead development of 6-FQs agents.

Design, Synthesis, Antibacterial Evaluation and Docking Study of Novel 2‐Hydroxy‐3‐(nitroimidazolyl)‐propyl‐derived Quinolone

“…was equal to reference drug. The results were in accordance with the reported finding that one of the promising hits originated from moxifloxacin chemical class (22,23).…”

“…Several quinolone hybrids displayed enhanced antibacterial activity against both Grampositive and Gram-negative organisms (13)(14)(15)(16)(17)(18)(19)(20). Recently, chemometric studies coupled with 3D structure-based molecular modeling approaches were conducted to explore the possibilities for the optimization of quinolone compounds, which also revealed that several novel fragments attached at 1 and 7 positions of those quinolones Research Article could provide a good accommodation for binding of the active site (22,23). All these stimulated us with great interest to focus on further structural modification at the C-7 position of quinolone in order to find novel quinolone derivatives with potential activity against bacterial strains including drug-resistant microorganisms.…”

Cluster‐based molecular docking study for in silico identification of novel 6‐fluoroquinolones as potential inhibitors against Mycobacterium tuberculosis

“…Conversely, the CombiLib library consisting of 427 drug‐like 6‐FQs (R 1 , R 7 ‐structural analogs of ciprofloxacin and moxifloxacin, as well as R 7 ‐structural analogs of ofloxacin) was obtained by using classical methodology for virtual combinatorial library design. [31, 32] The details of both libraries were discussed previously[28, 30] and therefore we give here only a brief summary.…”

“…The validated protein model with highest estimated discriminatory performances was subsequently used for generating the binding poses of a mixed virtual combinatorial drug‐like set of 427 analogs for which the biological activity values were predicted by using nonlinear chemometric strategy. [28]…”

Strategies for the Design and Discovery of Novel Antibiotics using Genetic Engineering and Genome Mining

“…1.1a). Combinatorial chemistry has also led to the development of novel antibiotics against S. aureus such as 3-aminoquinazolinediones (Hutchings et al 2008) or 6-fluoroquinolones (Ghosh and Bagchi 2011;Minovski et al 2012) active against Mycobacterium tuberculosis ( Fig. 1.1b).…”