Identification of the Seaweed Metabolites as Potential Anti-tubercular Agents Against Human Pantothenate synthetase: An In Silico Approach.

Tuberculosis is the disease which is caused due to the contagion of Mycobacterium tuberculosis. The multidrug resistance Mycobacterium tuberculosis is the main hassle in the treatment of this worldwide health threats. Pantothenate synthase is a legitimate goal for rational drug designing against Mycobacterium tuberculosis. The enzyme is most active in the presence of magnesium or manganese. Marine algal cell wall is rich in sulfated polysaccharides such as fucoidans (brown algae), κ-carrageenans (red algae), and ulvan (green algae) with various favorable biological activities such as anticoagulant, antiviral, antioxidative, anticancer, and immunomodulating activities. In this study, we have modeled binding modes of selected known anti-tubercular compounds and different solvent extract against pantothenate synthase using advanced docking program AutoDock 4.2 tool. In our current study, in silico experiments were carried out to determine if fucoidan, κ-carrageenan, and ulvan sulfated polysaccharides could be a potential target against PANc (pantothenate synthetase), with the goal of identifying potential inhibitors as anti-TB leads targeting PANc for further wet lab validation. Two bioactive compounds were docked to the Mtb pantothenate synthetase protein binding site, with docking scores ranging from - 5.57 to - 2.73. κ-carrageenan had the best pose and docking score, with a Ligand fit score of - 5.815. Ulvan did not dock with the protein. The molecular dynamics simulations were conducted with substrate and ligand bounded fucoidan and κ-carrageenan for 150 ns and the protein Mtb pantothenate synthetase showed a stable conformation in the simulation, with tight amino acid contributions binding to the ligand molecule. RMSD characterizes the conformation and stability of protein ligand complexes, with higher fluctuations indicating low stability and minimal low-level fluctuations indicating equilibration and stability. The graph for RMSF shows significant peaks due to fluctuations in active site regions and other peaks indicating the adaptation of the ligand molecule to the protein binding pocket. From the molecular dynamics study, it is clear that the compounds are having good binding affinity in the active site. The root mean square deviation, root mean square fluctuations, and radius of gyration are supportive evidences which helped us to conclude that the compounds κ-carrageenan and fucoidan are suitable lead molecules for inhibiting pantothenate synthetase. Based on these evidences, the natural compounds from seaweeds can be tested clinically either alone or in combinations against the protein, which could facilitate the designing or the synthesis of new lead molecules as drugs against the tuberculosis.