Molecular Docking Study, Drug-Likeness and Pharmacokinetic Properties (ADMET) Prediction of Some Novel Thiophene Derivatives as <i>Salmonella typhi</i> Inhibitors

Abstract

Typhoid fever is a gram- negative bacterial infection caused by the bacterium called Salmonella Typhi, a rod-like shaped pathogen. Salmonella typhi is both food-born and water-born pathogen. This disease is affecting people in both developed and underdeveloped countries. In this research, geometry optimization was carried out using density functional theory (DFT) at B3LYP/6-31G* level of theory in finding the most stable structures of all the studied molecules. Molecular docking studies was carried out on novel thiophene derivatives (anti-typhoid agents) against S. Typhi target (DNA gyrase B) with the pdb ID: 1TM2 to virtually screened the studied molecules. The drug-likeness and pharmacokinetic properties of the investigated molecules were also evaluated using SWISSADME and pkCSM online web tools, respectively. The molecular docking virtual screening carried out on the anti-typhoid agents has explored their theoretical binding affinities (which ranges between -7.1 to 7.8 kcal/mol) and poses with the active sites of the S. Typhi target (DNA gyrase B). Compound A11 with the highest binding affinity of -7.8 Kcal/mol interacted with the following amino acid residues LYS35, THR247, ASP166, VAL164, TRP170, ALA222, PHE41, TR266, ASP116 and PHE41 in the active site of the receptor via conventional hydrogen bond, carbon hydrogen bond, hydrophobic and electrostatic interactions, respectively. The drug-likeness of the studied compounds showed good response to the Lipinski’s rule of five filtering criterion by not violating more than one of the filtering criterion thereby confirming their drug-likeness properties and oral bioavailability, respectively. Their ADMET properties showed that they were all absorbed in the intestinal at a rate above 80% and well distributed in the brain and the central nervous system. They were all found to be both substrate and inhibitors of 3A4 which indicated their metabolic properties. And based on their predicted total clearance values, they can be excreted out. All the reported compounds had a negative AMES toxicity which mean they were all non-toxic. With reference been made to an approved already existing anti-typhoid agent ciprofloxacin with a binding affinity of -7.3 Kcal/mol to the investigated molecules (most especially compound A11), All the reported molecules have higher binding affinities than the ciprofloxacin, having good pharmacokinetic properties therefore proves the tendency of their effectiveness when been administered as drug.