Identification of inhibitor against H. pylori HtrA protease using structure-based virtual screening and molecular dynamics simulations approaches

The HtrA protease of Helicobacter pylori, which efficiently colonizes at the gastric epithelial of host cells, disrupts the mucosal integrity of E-cadherin and spreads inflammatory diseases including gastric cancer by cleaving the cell-cell adhesion of the host. The lack of knowledge on the molecular diversity, structural and functional behavior of HpHtrA necessitated the present study to explore its inhibition mechanism. At first, the similarity of HpHtrA with other gastro-intestinal pathogenic HtrA bacteria and its remote relationship with the Human HtrA homologs were ensured by the phylogenetic analysis and hence was identified as a novel therapeutic target for further design of inhibitors. The three dimensional structure of HpHtrA was modeled and simulated to achieve its stable conformation and was used as a receptor to screen for the possible lead compound through virtual screening (using ∼ 1.3 million compounds). Molecular dynamics simulations followed by the binding energy analysis revealed the affinity of the compound 300040 in forming a stable complex with HpHtrA and thereby revealed its potent role in inhibiting HpHtrA. It is also worthy to mention that, structurally, the ligand binding at the catalytic site of HpHtrA is mainly facilitated by the significant dynamics of L2 loop. Based on the present study, the hydroxyl-piperidine with 4-aminopiperidine scaffold is proposed to be one of the best possible lead compounds for the inhibition of H. pylori. [Display omitted] •HtrA protease from the class-I carcinogen H. pylori that expressed an evolutionarily distant relationship with human HtrAs, is selected as the target.•The modeled and simulated three dimensional structure of HpHtrA is used for virtual screening.•Top three hit compounds were identified through virtual screening and was compared with a reported lead compound.•The compound 300040 with hydroxyl-piperidine and 4-aminopiperidine scaffolds proposed as the potent lead against HpHtrA.