3,5-dinitrophenyl clubbed azoles against latent tuberculosis- a theoretical mechanistic study

Abstract: In this present study, novel series of dinitrophenyl linked azole compounds were designed keeping in view of the importance of azole molecules in combinations with nitro and amino group by hyphenation of these two pharmacophores as a single molecular scaffold against latent tuberculosis targeting Isocitrate Lyase (ICL) enzyme by using various computational tools. Our docking studies evidenced that all the novel designed compounds have the potential to inhibit the ICL enzyme with a binding energy in a range of -4.6 to -8.9 Kcal/mol. Moreover, all the designed compounds were predicted to be having promising ADMET parameters and found to be well in compliance with Lipinski‘s rule of five along with no toxicology profile. Among all the thirty five compounds tested, compound 3F is the best lead like molecule with -8.9 kcal/mol of binding energy compared to Rifampicin and 3-nitropropionate which has shown -8.1 kcal/mol and -4.6 Kcal/mol. Molecular dynamic simulation studies for compound 3F in complex with Isocitrate Lyase has elucidated several interesting molecular level protein-ligand interactions with some of the important amino acid residues present at the active binding site of ICL enzyme compared to Rifampicin and 3-nitropropionate. Conclusively, novel designed compound 3F of the present study have shown promising tuberculosis inhibition potential worth considering for further evaluations.