Exploring some substituted chalcones as DprE1 inhibitors for antitubercular activity: An integrated computational approach

Abstract The development of extensively drug resistance to Mycobacterium has further hindered WHO efforts in the fight against tuberculosis. Elucidation of new mechanistic pathways against drug-resistant TB is of primary concern. The current study aims to find potential chalcones via an in silico assessment against Decaprenylphosphoryl-β-D-ribose-2-oxidase (DprE1) which is a crucial target for finding antitubercular drug candidates. We prospected the in silico properties of a library of 30 chalcones having two aromatic rings and either an electron withdrawing or electron donating substituent against DprE1 enzyme. The results showed that the introduction of p-chloro or p-methyl substituents and an indole on the chalcones’ motif played critical roles in their inhibition of Mtb DprE1. These chalcones demonstrated favorable physicochemical, pharmacokinetic, and CYP metabolism characteristics, suggesting that they could be promising drug candidates for further investigation. Analysis of docked complexes revealed that non-covalent bonding interactions are important for the binding and stability of the chalcones within the active site of the protein with estimated free energy of binding ranging from -10.4 to -6.5 kcal/mol. The anti-TB sensitivity findings suggest that the compounds were more potent compared to the pyrazinamide against Mycobacterium tuberculosis. Furthermore, the binding stability study performed using molecular dynamics simulation of the DprE1-9C complex disclosed the conformational stability of the complex over 200 ns with average root mean square deviation not exceeding 0.25 nm (2.5 Å). The computational results could immensely contribute toward hit to lead triaging in the search for new DprE1 inhibitors with improved antitubercular activities.