Document Type : Original Research Article
Authors
1 Department of Chemistry, Federal University Lokoja, P.M.B., 1154, Lokoja, Kogi State, Nigeria
2 Department of Chemistry, Ahmadu Bello University, P.M.B. 1044, Zaria, Kaduna State Nigeria
Abstract
Typhoid fever, a disease caused by a Gram-negative bacterium known as Salmonella typhi constitutes a significant cause of morbidity and mortality, especially in developing nations. The rising cases of resistance to existing antibiotics by this bacterium have necessitated the search for the novel drug candidates. In this study, a data set of some anti-Salmonella typhi pyridine-substituted coumarins were subjected to Molecular Docking-based Virtual Screening against the active sites of DNA gyrase of the bacterium using EasyDock Vina 2.0 of AutoDock Vina software. Prior to the molecular docking calculation, the structures of the compounds were optimized using the DFT method of Spartan 14 software to obtain their minimum energy conformations. The outcome of the Virtual Screening led to the selection of compounds 12, 13, and 15 as template molecules for the design of more potent analogues because they bind better to the active sites of DNA gyrase target with binding affinity values (ΔG) of -9.6 kcal/mol, -9.5 kcal/mol and -9.6 kcal/mol, respectively. Subsequently, the template molecules were subjected to structural modifications leading to the design of more potent analogues with ΔG values ranging from -9.9 kcal/mol to -10.6 kcal/mol against DNA gyrase target. Furthermore, insilico drug-likeness and ADMET evaluation of the designed ligands revealed that they possess good oral bioavailability and positive pharmacokinetic profiles. It is hoped that the findings of this research would provide an excellent template for the development of novel drugs that could curb the alarming rate of resistance to existing antibiotics by Salmonella typhi.
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