journal article
Open Access Collection
Chemoinformatic Approaches to Identify Bioactive Inhibitors Against Type I Dehydroquinase (DHQ1) Enzyme of Typhoidal Salmonella
Ashfaq, Aqsa; Mariyam, Safah; Aziz, Ubair; Mukhtar, Mamuna; Andleeb, Saadia
doi: 10.1177/11779322261418889pmid: 42273065
The incidence of antibiotic resistance is critically jeopardizing the public health of the new millennium, affecting both clinical and therapeutic outcomes. Typhoid perforation in low- and middle-income countries (LMICs) is mostly caused by Salmonella typhi. The development of antibacterial therapies is drawn to the enzyme 3-dehydroquinate dehydratase type 1 (DHQ1), which is an important enzyme of the shikimate pathway in bacteria. Its role in the synthesis of chorismite, a natural precursor of the route leading to the synthesis of aromatic amino acids, validates it as an important therapeutic target. Therefore, the current work is based on the investigation of bioactive compounds that inhibit the crucial DHQ1 enzyme. Structure-based virtual screening (SBVS) and docking studies were done using AutoDock Vina tools to retrieve potential hit molecules with high binding affinity against DHQ1 from several ligand repositories. From a total of 551 compounds, 206 were filtered out for physicochemical properties, the Lipinski rule and subjected to molecular docking. A total of 10 ligands were selected with the highest binding affinities ranging from −9.8 to −9.1 (kcal/mol), ie, Cabotegravir, Imatinib, Prulifloxacin, Limonin, Silibinin, Atovaquone, Betamethasone Valerate, GSK1324726A, Isavuconazole, and Raltegravir. In addition, ADMET analysis, bioactivity prediction, and pharmacokinetic property prediction were carried out as prediction of activity spectra for substance (PASS) analysis to further prioritize the best inhibitory compound. Molecular dynamic simulations were used to verify the stability of the protein “DHQ1” docked with 3 hit ligands Cabotegravir, Limonin, and Silibinin by calculating root mean square fluctuation (RMSF), root mean square deviation (RMSD), radius of gyration (Rg), H-bond interaction, and molecular mechanics/generalized Born surface area (MM/GBSA) scores. Based on molecular dynamic (MD) simulations, it is reported that Cabotegravir and Limonin showed the optimal binding features with bacterial DHQ1 enzyme and can be deemed as a repurposed drug candidate as compared to Silibinin, which did not show favorable interactions with DHQ1 and needs to be explored further against typhoidal Salmonella.