Masoprocol

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a global public health threat, particularly due to dormant Mtb, which necessitates prolonged drug treatment. Mycobacterium tuberculosis malate synthase (MtbMS) is a key rate-limiting enzyme in the glyoxylate shunt, essential for the survival of dormant Mtb but absent in the host. Using target-based virtual screening and biochemical approaches, we identified novel natural inhibitors of MtbMS. Molecular docking by Schrödinger and subsequent manual selection identified 11 compounds as potential inhibitors. Molecular dynamics (MD) simulations and binding-free energy analysis (MM/GBSA) demonstrated high stability and binding affinity of MtbMS with Nordihydroguaiaretic Acids (NDGA) and Meso-NDGA. NDGA and Meso-NDGA by inhibition experiment exhibited half-maximal inhibitory concentrations (IC₅₀) against MtbMS at 1.10 ± 0.01 μM and 14.29 ± 0.95 μM and by Isothermal Titration Calorimetry (ITC) showed binding constants (K_d) of 5.66 μM and 34.90 μM, respectively. Their minimum inhibitory concentrations (MIC) against Mtb H37Rv were 60.47 μg/mL and 30.24 μg/mL, respectively. In conclusion, natural products NDGA and Meso-NDGA are potent inhibitors of MtbMS and represent promising new scaffolds for combating dormant Mtb.

The second most prevalent neurological disease among the elderly is Parkinson's disease, where neuroinflammation plays a significant role in its pathology. Purinergic signaling mediated by P2X7 plays a significant role in neuroinflammation and pyroptotic cell death pathways through mediators like NLRP3, Caspase-1, and Caspase-3, instigating pyroptotic cell death. No synthetic agent advanced in late-stage clinical trials due to their inefficacy and toxicity. Hence, in this study, we aimed to identify a phytoconstituent inhibitor against the hP2X7 receptor to ameliorate the inflammatory processes involved. To achieve this aim, we performed homology modeling of the receptor and screened phytoconstituents from a library of over 3500 commercially available phytoconstituents. Molecular docking through the Maestro program of the Schrödinger suite was performed considering evaluation parameters like docking score, docking pose and spatial arrangement, and MMGBSA binding free energy. Predictive pharmacokinetic and toxicity profiling was done using tools like QikProp, ADMETLab 2.0, SwissADME, and Protox-II. Molecular dynamic simulation was performed using Schrödinger's Desmond tool for the top 10 phytoconstituents. The complex stability was evaluated based on the ligand- and protein-RMSD, protein-ligand contact stability over a simulation period of 100 ns, protein RMSF, and ligand properties like RMSF, radius of gyration, intramolecular hydrogen bonding, and SASA. Based on the studies' results, silychristin, silybin, rosmarinic acid, nordihydroguaiaretic acid, and aurantiamide were shortlisted as the top 5 phytoconstituents against hP2X7. Further in-vitro and in-vivo studies would offer better clarity on the mechanism of action of these agents specifically related to pyroptotic cell death in various disease models.