Extraction of molecular features for the drug discovery targeting protein‐protein interaction of Helicobacter pylori CagA and tumor suppressor protein ASSP2

Abstract

Half of the world population is infected by the Gram‐negative bacterium Helicobacter pylori (H. pylori). It colonizes in the stomach and is associated with severe gastric pathologies including gastric cancer and peptic ulceration. The most virulent factor of H. pylori is the cytotoxin‐associated gene A (CagA) that is injected into the host cell. CagA interacts with several host proteins and alters their function, thereby causing several diseases. The most well‐known target of CagA is the tumor suppressor protein ASPP2. The subdomain I at the N‐terminus of CagA interacts with the proline‐rich motif of ASPP2. Here, in this study, we carried out alanine scanning mutagenesis and an extensive molecular dynamics simulation summing up to 3.8 μs to find out hot spot residues and discovered some new protein‐protein interaction (PPI)‐modulating molecules. Our findings are in line with previous biochemical studies and further suggested new residues that are crucial for binding. The alanine scanning showed that mutation of Y207 and T211 residues to alanine decreased the binding affinity. Likewise, dynamics simulation and molecular mechanics with generalized Born surface area (MMGBSA) analysis also showed the importance of these two residues at the interface. A four‐feature pharmacophore model was developed based on these two residues, and top 10 molecules were filtered from ZINC, NCI, and ChEMBL databases. The good binding affinity of the CHEMBL17319 and CHEMBL1183979 molecules shows the reliability of our adopted protocol for binding hot spot residues. We believe that our study provides a new insight for using CagA as the therapeutic target for gastric cancer treatment and provides a platform for a future experimental study.

Sequence variation of SARS-CoV-2 spike protein may facilitate stronger interaction with ACE2 promoting high infectivity

“…Modelling procedures for protein-protein docking and interface analyses were performed as previously described (11)(12)(13). Protein surface and patch analyses were performed in MOE suit (2019.0102) as described previously (14).…”

“…After temperature and pressure equilibration, MD simulation were carried out for 30ns for each system. Detailed procedure has been described in our previous studies (12,14).…”

Molecular Mechanisms and Treatment Strategies for Helicobacter pylori-Induced Gastric Carcinogenesis and Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma

“…(1) the activation of the oxidant-sensitive nuclear transcriptional factor kappa B via the classic pathway and alternatively through MAPK stimulation and (2) the activation of the pathway related to transcription factor AP-1. The interaction between cytosolic nucleotide binding and oligomerization domain 1 after delivery of H. pylori peptidoglycan in host cells for both mechanisms is essential [14] Although Ando et al reported that IL-8 expression is present in CagA-negative H. pylori genotypes [15], Peng et al observed the upregulation of IL-8 expression in both strains [16].…”

In Silico Prediction of Plasmodium falciparum Cytoadherence Inhibitors That Disrupt Interaction between gC1qR-DBLβ12 Complex

“…The negative value of the stability indicates the more stability of the complex. Hence, a positive value of the dStability shows the importance of the particular residue in the interface region of the complex structure [20,21]. Alanine Mutagenesis studies was conducted using MOE analyse the role of specific amino acid in the stability of the DBLβ12 and gC1qR [19].…”