Cheminformatics-enhanced discovery of therapeutic agents targeting isocitrate lyase in <i>Mycobacterium tuberculosis</i> infections

Tuberculosis (TB) is a global health challenge; therefore, there is an urgent requirement to develop a novel and more effective anti-TB therapeutic. This study targeted the isocitrate lyase (ICL) protein due to its pivotal role in the pathogenicity of <i>Mycobacterium tuberculosis</i> (Mtb). Virtual screening of 8752 bioactive compounds used an ML-based QSAR model and molecular docking. ADMET testing was performed on the top three hits to identify the compound most closely mimicking a drug molecule. The top hits, <b>648</b> and <b>2785758</b>, showed high binding affinity towards ICL with -7.3 and -7 kcal/mol, comparable to the control. These molecules also showed strong binding with the residue Asp108, which plays a vital role in ICL activity. Molecular dynamics simulations showed stability for <b>648</b> and <b>2785758</b>, comparable to the control compound used in this study. It was found that <b>648</b> bound to the protein maintained the RMSD constant and consistent at 0.3 nm for a complete 100 ns simulation. <b>2785758</b> showed a comparable RMSD trend to the control. Both <b>648</b> and <b>2785758</b> showed high RMSF for critical residue Asp108. Further, PCA and FEL confirmed the formation of a stable complex. MM/GBSA estimations of binding free energy indicated that compounds <b>648</b> had an elevated level of stability (Δ<i>G</i>_TOTAL = -28.11 kcal/mol) and <b>2785758</b> (Δ<i>G</i>_TOTAL = -21.05 kcal/mol). This study suggests that compounds <b>648</b> and <b>2785758</b> can potentially affect the activity of ICL, leading to its inactivation and ultimately preventing the progression of tuberculosis.