Identification of immucillin analogue natural compounds to inhibit MTAN through high throughput virtual screening and molecular dynamics simulation.

ABSTRACT

One in every two humans is having () in stomach causing gastric ulcer. Emergence of several drugs in eliminating has paved way for emergence of multidrug resistance in them. This resistance is thriving and thereby necessitating the need of a potent drug. Identifying a potential target for medication is crucial. Bacterial 5'-methylthioadenosine/-enosyl homocysteine nucleosidase (MTAN) is a multifunctional enzyme that controls seven essential metabolic pathways. It functions as a catalyst in the hydrolysis of the -ribosidic bond of adenosine-based metabolites: -adenosylhomocysteine (SAH), 5'-methylthioadenosine (MTA), 5'-deoxyadenosine (5'-DOA), and 6-amino-6-deoxyfutalosine. unlike other bacteria and humans utilises an alternative pathway for menaquinone synthesis. It utilises Futosiline pathway for menaquinone synthesis which are obligatory component in electron transport pathway. Therefore, the enzymes functioning in this pathway represent them-self as a point of attack for new medications. We targeted MTAN protein of to find out a potent natural hit to inhibit its growth A comparative analysis was made with potent MTAN (MTAN) known inhibitor, 5'-butylthio-DADMe-Immucillin-A (BuT-DADMe-ImmA) and ZINC natural subset database. Optimized ligands from the ZINC natural database were virtually screened using ligand based pharmacophore hypothesis to obtain the most efficient and potent inhibitors for MTAN. The screened leads were evaluated for their therapeutic likeness. Furthermore, the ligands that passed the test were subjected for MM-GBSA with MTAN to reveal the essential features that contributes selectivity. The results showed that Van der Waals contributions play a central role in determining the selectivity of MTAN. Molecular dynamics (MD) studies were carried out for 100 ns to assess the stability of ligands in the active site. MD analysis showed that binding of ZINC00490333 with MTAN is stable compared to reference inhibitor molecule BuT-DADMe-ImmA. Among the natural inhibitors screened after various docking procedures ZINC00490333 has highest binding score for MTAN (- 13.987). The ZINC inhibitor was successful in reproducing the BuT-DADMe-ImmA interactions with MTAN. Hence we suggest that ZINC00490333 compound may represent as a good lead in designing novel potent inhibitors of MTAN. This in silico approach indicates the potential of this molecule for advancing a further step in gastric ulcer treatment.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s40203-021-00081-2.