MOLECULAR DOCKING AND IN SILICO EVALUATION OF ISOCHAETOMININE AS A NOVEL INHIBITOR OF HELICOBACTER PYLORI UREASE (1E9Y)

Abstract

Helicobacter pylori is an important gastric pathogen that uses the virulent urease enzyme to survive in the acidic environment of the human stomach. Urease hydrolyzes urea to generate ammonia. This increases the local pH and allows the bacterium to colonize the gastric mucosa and establish a long-term infection. Therefore, urease is considered a central virulence factor in H. pylori pathogenesis. And targeting this enzyme is a promising strategy in anti-H. pylori drug discovery. [3] [11] In this thesis Isochaetominine is shown as a novel natural inhibitor against H. pylori urease (PDB ID: 1E9Y). The study is based on my conference paper, in which insilco experiments were conducted, where 2431 natural compounds were virtual screened using PyRx/AutoDock Vina and ADME profiling was analysed using SwissADME. In docking results, Isochaetominine showed the strongest binding affinity (-9.3 kcal/mol), that was superior to Protocatechuic acid (-5.9 kcal/mol) and Acetohydroxamic acid (-4.9 kcal/mol). Validation of our experiment was done using these two known inhibitors, PCA and AHA. These results suggest that Isochaetomine may fit better into the active site and be a stronger lead scaffold for urease inhibition. Isochaetominine is a naturally occurring indole alkaloid, a compound of fungal origin, due to its rigid cage-like structure, nitrogen-rich framework, and hydrophobic features. It creates interest in biologically active molecules.The major advantage of using natural products is that they are more effective than synthetic inhibitors. Provides better biocompatibility, lower toxicity risk, and greater structural diversity. Natural compounds have also been repeatedly highlighted in the literature on urease inhibitors as safer alternatives. [10] In ADME analysis, Isochaetominine has shown high gastrointestinal absorption, no BBB permeability, no CYP isoenzyme inhibition, and acceptable drug-likeness. PCA showed some medicinal chemistry alerts and CYP isoenzyme inhibition issues. Whereas AHA, even after being highly soluble, is linked to toxicity related concerns. On this basis Isochaetominine can be considered a promising anti-urease candidate for further in vitro and in vivo validation.