Abstract
The characteristic of interaction with various enzymes and processivity-promoting nature during DNA replication makes β-clamp an important drug target. Helicobacter pylori (H. pylori) have several unique features in DNA replication machinery that makes it different from other microorganisms. To find out whether difference in DNA replication proteins behavior accounts for any difference in drug response when compared to E. coli, in the present study, we have tested E. coli β-clamp inhibitor molecules against H. pylori β-clamp. Various approaches were used to test the binding of inhibitors to H. pylori β-clamp including docking, surface competition assay, complex structure determination, as well as antimicrobial assay. Out of five shortlisted inhibitor molecules on the basis of docking score, three molecules, 5-chloroisatin, carprofen, and 3,4-difluorobenzamide were co-crystallized with H. pylori β-clamp and the structures show that they bind at the protein-protein interaction site as expected. In vivo studies showed only two molecules, 5-chloroisatin, and 3,4-difluorobenzamide inhibited the growth of the pylori with MIC values in micro molar range, which is better than the inhibitory effect of the same drugs on E. coli. Therefore, the evaluation of such drugs against H. pylori may explore the possibility to use to generate species-specific pharmacophore for development of new drugs against H. pylori.
Highlights
There are certain pathogens that are affecting the human population worldwide
We found some differences at DNA binding as well as protein binding regions in native Hpβ-clamp when compared to other β-clamp structures from various organisms [16]
This made us think whether there is any difference in binding pattern of inhibitors or the drugs that are already known to inhibit E. coli β-clamp could inhibit H. pylori β clamp
Summary
There are certain pathogens that are affecting the human population worldwide. Helicobacter pylori (H. pylori) is one of them that infects around 50% of the world’s population by causing peptic ulcer, gastritis, and gastric cancer [1]. Where Z represents any amino acid which is hydrophilic in nature while X represents any small hydrophobic residue This protein-protein interaction site has been target for drug development in different organisms. We found some differences at DNA binding as well as protein binding regions in native Hpβ-clamp when compared to other β-clamp structures from various organisms [16] This made us think whether there is any difference in binding pattern of inhibitors or the drugs that are already known to inhibit E. coli β-clamp could inhibit H. pylori β clamp . All of the five molecules showed competitive binding with ligase and three of them were co-crystallized and determined the complex structure with Hpβ-clamp to show that they bind to the ligase binding site/protein-protein interaction site.
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