Design of Potential Urease inhibitors via Pharmacophore and DockingBased Virtual Screening

Urease (urea amidohydrolase, EC ۳.۵.۱.۵), belong to the superfamily of amidohydrolases and phosphotriesterases, that hydrolyzes urea to CO۲ and NH۳ at a very high speed. Urease is essential for the growth and survival of bacteria such as Helicobacter pylori in acidic milieu of stomach, as it helps to increase the pH of the environment. H.pylori is a gram-negative, microaerophilic spiral bacterium is a common chronic pathogen found in humans, leading to the development of diseases such as chronic gastritis, gastric ulcer, and gastric cancer. Other pathological conditions associated with urease activity include renal lithiasis, hepatic coma, encephalopathy, and pyelonephritis. Therefore, inhibition of this enzyme can be very effective in inhibiting and controlling of H.pylori infection. Hence, there has been considerable interest in uncovering novel urease inhibitors with good bioavailability and minimal toxicity. Today, computer-aided drug design is becoming more widespread due to its swiftness, cost-e↵ectiveness, and precision. This investigation has been embraced a hybrid approach that included docking and virtual screening to identify new urease inhibitors. Method:The crystal structure of Jack bean urease, with the PDB ID of ۴h۹m, was achieved from Protein Data Bank (www.rcsb.org). A proper pharmacophore model was generated using Ligand Scout ۳.۱۲ on the most critical area on the urease active site. Then ZINC libraries (over ۳۵ million compounds) were applied for virtual screening. Results and Discussion:Obtained compounds from virtual screening were followed by molecular docking studies. Six compounds were selected based on docking score and complying with Lipinski’s “rule of five”. Selected compounds can be considered as a proper candidate in order to develop new urease inhibitors

کلیدواژه ها:

Virtual Screening ، Molecular Docking ، Urease ، Inhibitor