Insightful chemistry of molecular docking studies and ADMET profiling of 4-amino-1,2,4-triazole scaffolds as potential inhibitor of DprE1 enzymes as antitubercular agents

Airborne transmission of the bacterial illness tuberculosis (TB) is attributed to Mycobacterium tuberculosis (Mtb). Mycobacterium tuberculosis, a multidrug-resistant strain, spreads quickly and is the cause of multidrug-resistant tuberculosis (MDRTB). A study was conducted to investigate the possible antitubercular interactions between produced 4-amino-1,2,4-triazole scaffolds and the DprE1 enzyme in mycobacterium. The binding affinity of ligands with the target PDB ID 6hfw was predicted using Pyrex 0.8 version software. Normal mode analysis and RMSF of protein–ligand complexes were performed using the imods server and CABSflex server. The Stoptox and Pkcsm servers were used to forecast the drug-likeness and toxicity of ligands. C20 has a significant negative binding energy of −10.4 kcal/mol and eight conventional hydrogen bonds, indicating a strong binding affinity for DprE1. In contrast, the reference medication isoniazid has a significantly lower binding affinity with two conventional hydrogen bonds of −5.5 kcal/mol. The binding energies of the remaining compounds, C21, C22, and C23, were −10.3 kcal/mol, correspondingly. Additionally, the absorption, distribution, metabolism, and excretion (ADME) features of designed compounds were assessed, showing the possibility for further development into more effective anti-tubercular medicines. As a result, compounds C20, C21, C22, C23, and C24 are the best candidates as DprE1 enzyme protein inhibitors; however, in-vitro animal studies and toxicity studies are required to confirm these findings.