Targeting Cytotoxin-Associated Antigen A, a Virulent Factor of Helicobacter pylori-Associated Gastric Cancer: Structure-Based In Silico Screening of Natural Compounds

Abstract

Gastric cancer is the fifth most frequent cancer and the third major cause of mortality worldwide. Helicobacter pylori, a bacterial infection linked with GC, injects the cytotoxin-associated antigen A (CagA; an oncoprotein) into host cells. When the phosphorylated CagA protein enters the cell, it attaches to other cellular components, interfering with normal cellular signaling pathways. CagA plays an important role in the progression of GC by interacting with phosphatidylserine of the host cell membrane. Therefore, disrupting the CagA–phosphatidylserine connection using small molecules appears to be a promising therapeutic approach. In this report, we screened the natural compounds from ZINC database against the CagA protein using the bioinformatics tools. Hits were initially chosen based on their physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics, as well as other drug-like characteristics. To locate safe and effective hits, the PAINS filter, binding affinities estimation, and interaction analysis were used. Three compounds with high binding affinity and specificity for the CagA binding pocket were discovered. The final hits, ZINC153731, ZINC69482055, and ZINC164387, were found to bind strongly with CagA protein, with binding energies of -11.53, -10.67, and -9.21 kcal/mol, respectively, which were higher than that of the control compound (-7.25 kcal/mol). Further, based on binding affinity and interaction pattern, two leads (ZINC153731, ZINC69482055) were chosen for molecular dynamics (MD) simulation analysis. MD results showed that they displayed stability in their vicinity at 100 ns. This study suggested that these compounds could be used as possible inhibitors of CagA protein in the fight against GC. However, additional benchwork tests are required to validate them as CagA protein inhibitors.

The effects and mechanisms of natural products on Helicobacter pylori eradication

“…With the advances of new technologies such as virtual screening, bioinformatics, and artificial intelligence, bioprospecting is currently equipped with innovative powerful tools and undergoing rapid evolution. For instance, in the work of He et al., virtual screening and molecular modeling were utilized to identify ligands that interact with CagA protein to discover potential natural compound candidates ( He et al., 2022a ). Bioinformatics approaches, including genomics, proteomics, and metabolomics, are also widely implemented in natural product biosynthesis and production, and some researchers bet on artificial intelligence projects for drug innovation inspiration ( Ngo et al., 2013 ; Merwin et al., 2020 ; Zhang et al., 2020 ).…”

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“…It is microaerophilic, requiring carbon dioxide and reduced oxygen concentration for growth. It raises the gastric pH by converting urea to ammonia and carbon dioxide [2,3].…”

“…H.pylori can be transmitted from person to person through direct contact with saliva and faeces, as well as contaminated food and water. [3].…”

“…The enzyme is responsible for urea degradation to ammonia and carbon dioxide. The leading cause of ulcers is when the bacteria attack the lining that protects the stomach and make an enzyme called urease [3]. H.pylori strains have a high molecular mass protein encoded by cagA and vacuolating toxin encoded by vacA.…”

“…Currently, there are several diagnostic approaches for detecting the presence of this infection, each with its own set of benefits, drawbacks, and limitations. On tissue obtained by endoscopy, biopsy-based procedures such as polymerase chain reaction (PCR), histological examination, culture, and the fast urease test (cod liver oil test/CLO 2 test) are performed [3]. On the other hand, non-invasive methods include the urea breath test (C13-C14), serology to find IgG antibodies, and stool antigen test (SAT).…”