Computational insights into the role of structurally diverse plant secondary metabolites as inhibitors against Imidazole Glycerol Phosphate Dehydratase of Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) is one of the major causes of death worldwide and there is a pressing need for the development of novel drug leads. The Imidazole Glycerol Phosphate Dehydratase (IGPD) of Mtb is one of the key enzymes in the histidine biosynthesis pathway and has been recognized as the potentially underexploited drug target for anti-tuberculosis treatment. In the present study, 6063 structurally diverse plant secondary metabolites (PSM) were screened for their efficiency in inhibiting the catalytic activity of IGPD through molecular docking. The top 150 PSMs with the lowest binding energy represent the chemical classes, including Tannins (34%), Flavonoid Glycosides (14%), Terpene Glycosides (10%), Steroid Lactones (9.3%), Flavonoids (6.6%), Steroidal Glycosides (4.6%), etc. Bismahanine, Ashwagandhanolide, and Daurisoline form stable IGPD-inhibitor complexes with binding free energies of -291.3 ± 16.5, -279.0 ± 25.0, and -279.8 ± 17.6 KJ/mol, respectively, as determined by molecular dynamics simulations. These PSM demonstrated strong H-bond interactions with the amino acid residues Ile279, Arg281, and Lys276 in the catalytic region of IGPD, as revealed by structural snapshots. On the basis of our findings, these three PSM could be considered as possible leads against IGPD and should be explored in vitro and in vivo.Communicated by Ramaswamy H. Sarma.

Comments:

It seems like you are presenting the summary of a scientific study related to the potential use of plant secondary metabolites (PSM) as inhibitors of the Imidazole Glycerol Phosphate Dehydratase (IGPD) in Mycobacterium tuberculosis (Mtb). In this study, 6063 structurally diverse plant secondary metabolites were screened for their ability to inhibit IGPD through molecular docking. The top 150 PSMs, belonging to various chemical classes such as tannins, flavonoids, terpenes, and steroidal lactones, were identified as potential inhibitors.

Among these, three PSMs - Bismahanine, Ashwagandhanolide, and Daurisoline - were found to form stable complexes with IGPD, exhibiting strong hydrogen bond interactions with specific amino acid residues in the catalytic region of IGPD. Molecular dynamics simulations were used to determine the binding free energies of these complexes, with values of -291.3 ± 16.5, -279.0 ± 25.0, and -279.8 ± 17.6 kJ/mol, respectively.

Based on these findings, these three PSMs have been suggested as possible leads against IGPD and are recommended for further exploration through in vitro and in vivo studies. The results indicate a promising avenue for the development of novel drugs targeting Mtb, a significant step in the ongoing efforts to combat tuberculosis.