Marmin-Derivatives as Promising Inhibitors of Cysteine Synthases from <i>Mycobacterium Tuberculosis</i>: An <i>in silico</i> Approach

L-Cysteine plays a crucial role in providing redox defense to Mycobacterium tuberculosis (Mtb) against reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI) generated by host macrophages during the persistent phase. De novo biosynthesis of L-Cysteine in Mtb is catalyzed by three cysteine synthases, viz., CysK1, CysM and CysK2. Our previous research explored and identified a natural coumarin compound, Marmin, as an ideal inhibitor of all three mycobacterial cysteine synthases. Withal, Marmin possesses dual merits of being effective against active and dormant Mtb. These beneficial attributes of Marmin prompted us to design Marmin derivatives and to investigate their inhibitory activities toward Mtb cysteine synthases in silico.This study generated 60 Marmin derivatives and evaluated their ADMET properties, binding efficiencies, interaction profiles, and stabilities of protein–ligand (PL) complexes using in silico tools. The most potent inhibitor, M59, displayed an average binding energy (BE) value of −7.7 kcal/mol, and an inhibition constant (IC50) value of 3.3 [Formula: see text]M against the target enzymes, with a reduction in carcinogenicity and cytotoxicity compared to the native compound Marmin. The lead did not show an increase in synthetic accessibility, signifying the potency of the compound to be developed as an inhibitor with activity against all three mycobacterial cysteine synthases.