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

Shan He,Haitham Ali M Alzghaibi,Ali H Alharbi,Hamsa Jameel Banjer,Abdulraheem Ali Almalki,Ibtesam S Al-Dhuayan,Ziaullah M Sain,Mashael M Alnamshan,Yang Zhang,Qazi Mohammad Sajid Jamal,Farah Anjum,Amany I Alqosaibi,Misbahuddin M Rafeeq,Abdul Rahaman

doi:10.3390/molecules27030732

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.

Highlights

Gastric cancer (GC) is the 5th most prevalent malignancy and the 3rd largest cause of cancer mortality, accounting for about 0.8 million deaths globally in 2018
cytotoxin-associated antigen A (CagA) is the only oncoprotein that has been demonstrated to be transported by H. pylori
CagA acts as a bacterium-derived scaffolding/adaptor protein inside the host cell, causing gastric mucosa carcinogenesis [7]

Summary

Introduction

Gastric cancer (GC) is the 5th most prevalent malignancy and the 3rd largest cause of cancer mortality, accounting for about 0.8 million deaths globally in 2018. Helicobacter pylori, the causal agent of GC, is a Gram-negative microaerophilic bacterium that infects the stomach epithelium [2,3] and has been shown to infect nearly half of the world’s population, making it one of the most prevalent human infectious agents globally [4,5]. H. pylori injects the cytotoxin-associated antigen A (CagA; an oncoprotein) into host cells via the cag Type IV secretion system [6]. CagA acts as a bacterium-derived scaffolding/adaptor protein inside the host cell, causing gastric mucosa carcinogenesis [7]. Given that the contact between the CagA protein and the membrane phosphatidylserine (PS) is essential for CagA protein entrance into the host cell, blocking the interaction with small molecules looks to be a viable therapeutic approach [7,10]

Objectives

Methods

Results