Exploring

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health burden due to its ability to persist in a latent drug-tolerant state. During latency, Mtb relies on host lipids and activates the glyoxylate shunt to bypass carbon-loss steps of the tricarboxylic acid cycle. This pathway is driven by isocitrate lyase (ICL), present as two isoforms, ICL1 and ICL2. While ICL1 functions as the primary catalytic enzyme, ICL2 contains a distinct C-terminal regulatory Domain IV where acetyl-CoA binds and allosterically enhances enzymatic activity, promoting lipid-dependent persistence. Given that this regulatory pocket is structurally independent of the catalytic center, it offers a selective target for allosteric inhibition of the persistent-associated factor. Phytochemicals from Andrographis paniculata (Kalmegh), a plant known for antimycobacterial activity, were therefore investigated as potential modulators of ICL2. Molecular docking against the acetyl-CoA-binding Domain IV, followed by in silico ADMET and ProTox-3 toxicity prediction, identified candidates capable of interfering with acetyl-CoA-mediated activation. Notably, several plant-derived bioactives exhibited higher predicted binding affinity than acetyl-CoA at the regulatory pocket across both open and closed conformational states, along with favourable pharmacokinetic and toxicity profiles. These findings support allosteric targeting of ICL2 as a structurally informed strategy to disrupt lipid-dependent persistence and provide candidate scaffolds for future anti-latency therapeutic development.