Cheminformatics-enhanced discovery of therapeutic agents targeting isocitrate lyase in Mycobacterium tuberculosis 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 Mycobacterium tuberculosis (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, 648 and 2785758, 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 648 and 2785758, comparable to the control compound used in this study. It was found that 648 bound to the protein maintained the RMSD constant and consistent at 0.3 nm for a complete 100 ns simulation. 2785758 showed a comparable RMSD trend to the control. Both 648 and 2785758 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 648 had an elevated level of stability (ΔG_TOTAL = -28.11 kcal/mol) and 2785758 (ΔG_TOTAL = -21.05 kcal/mol). This study suggests that compounds 648 and 2785758 can potentially affect the activity of ICL, leading to its inactivation and ultimately preventing the progression of tuberculosis.