Pyrazine Linked 1,3,4-Oxadiazoles as DNA Gyrase Inhibitors: In silico Design, Molecular Docking, MM-GBSA Assay, MD Simulations and ADMET studies

The recent surge in multi-drug-resistant organisms has led to millions of infections and deaths worldwide, highlighting the urgent need for novel antimicrobial agents. In response, this study aims to investigate the designed hybrid molecules of 1,3,4-oxadiazole-pyrazine derivatives (P1–15) and to assess their potential as DNA gyrase inhibitors through in silico approach. All the designed compounds were in compliance with Lipinski’s rule for drug-likeness, ADMET profile. Further molecular docking studies revealed that compounds P1 (−6.94 kcal/mol), P2 (−6.50 kcal/mol), demonstrated superior binding affinities, surpassing standard drug Novobiocin (−5.79 kcal/mol). The calculations related to MM-GBSA showed favorable free binding energy. A 200 ns MD simulations for P1 and standard Novobiocin were conducted to identify the key interactions occurring within the protein–ligand complexes. Based on these results, this study indicates that these compounds can be utilized to develop new antimicrobial agents by incorporating preferred structural modifications.