Computational Studies to Identify Potential Inhibitors Targeting the DprE1 Protein in Mycobacterium tuberculosis

Abstract

Background: DprE1, which is a flavoenzyme, is very important for cell wall biosynthesis in Mycobacterium tuberculosis (Mtb) and for the pathogenesis, virulence, lethality, and stress resistance of the host. Drug-resistant tuberculosis is a challenging global human health issue, necessitating the development of novel, more effective treatment regimens without adverse effects. DprE1 represents a potential therapeutic target. It was explored as a drug target utilizing benzothiazoles (BTZ), which are enormously potential anti-bacterial agents and are currently being explored as anti-mycobacterial entities. Materials and Methods: We used virtual screening of bioactive molecules from PubChem and ZINC databases targeting DprE1, having bioactive thousands of molecules known for anti-microbial activity. In the present study, we selected 100 compounds as the most promising candidates to act as potential DprE1 inhibitors to control this emerging condition of tuberculosis infection. To identify the six topranked compounds, molecular docking was used to calculate the binding affinities (ranging from -8.3 to 10.0 kcal/mol) between various compounds (C1-C6) and the DprE1 protein.Results: Based on the results of an ADMET analysis, these six chemicals are safer potential drug candidates, as neither AMES toxicity nor carcinogenicity is present when toxicological properties are considered. Out of 6 compounds, the top-ranked compound exhibiting the best binding affinity against the drug target DprE1 (Pdb-id;4FEH) receptor was further subjected to molecular dynamic simulation for 100 nanoseconds to check the stability and trajectories by root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) graphs and interacting coordinates using Desmond Schrodinger Software. Conclusion: Our in-silico investigation identified potent inhibitors for the DprE1 protein of Mtb, and these compounds can be considered and recommended as the lead molecules in the treatment of tuberculosis.

Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against Mycobacterium tuberculosis and Hit Validation by Biological Assays

“…However, optimization of a lead compound, involving selection of structural modifications followed by synthesis and biological assay, can be both time-consuming and budget-intensive. In contrast, virtual screening can be a cost-effective and time-saving technique for discovery of new compounds. − This approach has been successfully used to identify multiple candidate anti-tuberculosis agents including inhibitors of PknB, PknG, DprE1, MurB, RpfB, DXPS, PimA, and CtpF. − Based on these promising previous findings, the indole derivative G24 was utilized as the starting template for structural similarity searches, constituting the initial step in the virtual screening approach used in the present work. These identified multiple candidate ATPase inhibitors from the compound library of the Specs database (www.specs.net).…”