Clodronic Acid has Strong Inhibitory Interactions with the Urease Enzyme of Helicobacter Pylori: Computer-aided Design and in vitro Confirmation.
Helicobacter pylori
approved small molecule drugs
clodronic acid.
docking
urease
Journal
Current computer-aided drug design
ISSN: 1875-6697
Titre abrégé: Curr Comput Aided Drug Des
Pays: United Arab Emirates
ID NLM: 101265750
Informations de publication
Date de publication:
10 Nov 2023
10 Nov 2023
Historique:
received:
12
07
2023
revised:
11
09
2023
accepted:
20
09
2023
medline:
14
11
2023
pubmed:
14
11
2023
entrez:
14
11
2023
Statut:
aheadofprint
Résumé
Helicobacter Pylori (HP) infection could lead to various gastrointestinal diseases. Urease is the most important virulence factor of HP. It protects the bacterium against gastric acid. Therefore, we aimed to design urease inhibitors as drugs against HP infection. The DrugBank-approved library was assigned with 3D conformations and the structure of the urease was prepared. Using a re-docking strategy, the proper settings were determined for docking by PyRx and GOLD software. Virtual screening was performed to select the best inhibitory drugs based on binding affinity, FitnessScore, and binding orientation to critical amino acids of the active site. The best inhibitory drug was then evaluated by IC50 and the diameter of the zone of inhibition for bacterial growth. The structures of prepared drugs were screened against urease structure using the determined settings. Clodronic acid was determined to be the best-identified drug, due to higher PyRx binding energy, better GOLD FitnessScore, and interaction with critical amino acids of urease. In vitro results were also in line with the computational data. IC50 values of Clodronic acid and Acetohydroxamic Acid (AHA) were 29.78 ± 1.13 and 47.29 ± 2.06 μg/ml, respectively. Diameters of the zones of inhibition were 18 and 15 mm for Clodronic acid and AHA, respectively. Clodronic acid has better HP urease inhibition potential than AHA. Given its approved status, the development of a repurposed drug based on Clodronic acid would require less time and cost. Further, in vivo studies would unveil the efficacy of Clodronic acid as a urease inhibitor.
Sections du résumé
BACKGROUND
BACKGROUND
Helicobacter Pylori (HP) infection could lead to various gastrointestinal diseases. Urease is the most important virulence factor of HP. It protects the bacterium against gastric acid.
OBJECTIVE
OBJECTIVE
Therefore, we aimed to design urease inhibitors as drugs against HP infection.
METHODS
METHODS
The DrugBank-approved library was assigned with 3D conformations and the structure of the urease was prepared. Using a re-docking strategy, the proper settings were determined for docking by PyRx and GOLD software. Virtual screening was performed to select the best inhibitory drugs based on binding affinity, FitnessScore, and binding orientation to critical amino acids of the active site. The best inhibitory drug was then evaluated by IC50 and the diameter of the zone of inhibition for bacterial growth.
RESULTS
RESULTS
The structures of prepared drugs were screened against urease structure using the determined settings. Clodronic acid was determined to be the best-identified drug, due to higher PyRx binding energy, better GOLD FitnessScore, and interaction with critical amino acids of urease. In vitro results were also in line with the computational data. IC50 values of Clodronic acid and Acetohydroxamic Acid (AHA) were 29.78 ± 1.13 and 47.29 ± 2.06 μg/ml, respectively. Diameters of the zones of inhibition were 18 and 15 mm for Clodronic acid and AHA, respectively.
CONCLUSION
CONCLUSIONS
Clodronic acid has better HP urease inhibition potential than AHA. Given its approved status, the development of a repurposed drug based on Clodronic acid would require less time and cost. Further, in vivo studies would unveil the efficacy of Clodronic acid as a urease inhibitor.
Identifiants
pubmed: 37957909
pii: CAD-EPUB-136071
doi: 10.2174/0115734099271837231026064439
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.