Virtual screening of novel pyridine derivatives as effective inhibitors of DNA gyrase (GyrA) of salmonella typhi

Abstract

In a bid to discovering novel antibiotics to combat growing trend of multi-drug resistance strains of Salmonella typhi, 48 new pyridine derivatives with significant inhibitory activities against the aforementioned bacterium were subjected to molecular docking against DNA gyrase protease of the bacterium, drug likeness evaluation and pharmacokinetics profiling. All the 48 leads displayed better binding affinity values when compared with Amoxicillin, Ciprofloxacin, Ceftriaxone, Ampicillin, and chloramphenicol, the standard antibiotics used herein for quality assurance. Furthermore, the majority of the compounds were, however, screened out due to their poor pharmacokinetics profiles and drug-likeness. Only five compounds emerged as the most promising leads and they include C4 with binding affinity of -8.0 kcal/mol, C8 (-8.6 kcal/mol), C9 (-8.1 kcal/mol), C26 (-8.3 kcal/mol), and C27 (-8.0 kcal/mol). These compounds not only displayed better binding affinity when compared with the reference antibiotics but also exhibit different modes of interactions with the target protease of the bacterium making them more potent and drug like. Toxicity evaluation of the leads also revealed that the compounds are neither tumorigenic nor mutagenic. In view of the excellent binding affinity, high pharmacokinetics profile and positive drug-likeness of the novel ligands, we recommend these promising compounds for in vitro and in vivo studies in order to discover novel antibiotics that could curb the dangerous trend of multiple drug resistance by Salmonella typhi.

Isolation, Characterization, Antimicrobial and Theoretical Investigation of Some Bioactive Compounds Obtained from the Bulbs of Calotropisprocera

“…Oral bioavailability (drug-likeness) prediction for therapeutic ligands is a fundamental evaluation in novel drug discovery and development owing to the fact that oral delivery remains the most common path of drug delivery into the systemic circulation [34]. This essential parameter was assessed for the two phytochemicals taking cognisance of Lipinski's rule of five and the Veber's rule.…”

“…The target protein was further processed via the addition of Polar hydrogens and Kollman charges with the aid of Auto Dock Vina tool v1.5.7. Finally, the docking calculation between the ligands and the target DNA gyrase was performed using PyRx software of Auto Dock Vina tool by centring the Vina search space at X: -26.4401 Å, Y: 23.0598 Åand Z: 22.0813 Åwith dimensions of X: 51.6292 Å, Y: 53.0044 Åand Z: 51.8136 Å [26][27][33][34].…”

“…Veber's rule, on the other hand stipulates that, for a drug to be orally bioavailable, the number of rotatable bonds (NRB) must be < 10 and topological polar surface area (TPSA) must be < 140 Å 2 . The NRB, TPSA, MW, HBD, HBA, and Log P value of the bioactive ligands were computed using the Swiss ADME (http: //www.swissadme.ch/www.swissadme.ch/) online tool [26][27][33][34].…”

“…The phytochemicals were profiled for their gastrointestinal (GI) absorption, blood brain barrier (BBB) permeation, P-glycoprotein (P-gp) substrate potentials, and cytochrome-P450 enzymes inhibition using the Swiss ADME online server at http://www.swissadme.ch/ index.php. Furthermore, Osiris Data Warrior V5.5.0 chemoinformatics program was used to perform in silico toxicity assay on the ligands using the following toxicity endpoints; mutagenicity, reproductive effect, and irritating effect [26][27][33][34].…”