Predictive profiling of gram-negative antibiotics in CagA oncoprotein inactivation: a molecular dynamics simulation approach

ABSTRACT

Gastric cancer (GC) is the fifth most prevalent form of cancer worldwide. CagA - positive Helicobacter pylori infects more than 60% of the human population. Moreover, chronic infection of CagA-positive H. pylori can directly affect GC incidence. In the current study, we have repurposed FDA-approved antibiotics that are viable alternatives to current regimens and can potentially be used as combination therapy against the CagA of H. pylori. The 100 FDA-approved gram negative antibiotics were screened against CagA protein using the AutoDock 4.2 tool. Further, top nine compounds were selected based on higher binding affinity with CagA. The trajectory analysis of MD simulations reflected that binding of these drugs with CagA stabilizes the system. Nonetheless, atomic density map and principal component analysis also support the notion of stable binding of antibiotics to the protein. The residues ASP96, GLN100, PRO184, and THR185 of compound cefpiramide, doxycycline, delafloxacin, metacycline, oxytetracycline, and ertapenem were involved in the binding with CagA protein. These residues are crucial for the CagA that aids in entry or pathogenesis of the bacterium. The screened FDA-approved antibiotics have a potential druggability to inhibit CagA and reduce the progression of H. pylori borne diseases.

KEYWORDS:

• Antimicrobial resistance (AMR)
• Helicobacter pylori
• cytotoxin associated protein A (CagA)
• molecular dynamics simulation
• FDA-approved antibiotics

Acknowledgments

We gratefully acknowledge the DST-FIST Project No. SR/FST/LS-I/2020/621 and Indian Institute of Technology Indore for providing facilities and support. This project was supported by the Department of Science and Technology DST-EMR project no. DST-EMR: EMR/2017/001637. SK acknowledge the Department of Biotechnology, Govt. of India for BIC project grant (BT/PR40161/BTIS/137/32/2021) and SKB acknowledge National Institute of Pharmaceutical Education and Research (NIPER)- Ahmedabad. We are thankful to CSIR, DST-Inspire and DBT for fellowship to Dharmendra Kashyap, Nidhi Varshney and Vaishali Saini, respectively, in the form of a research stipend. We appreciate Budhadev Baral, Pranit Bagde, Anushka Mukherjee, Annu Rani, Meenakshi Kandpal, Dr Tarun Prakash Verma, Samiksha Rele, Siddharth Singh, Sonali Adhikari, Akreti Tandon and our other lab colleagues for insightful discussions and advice.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2023.2230876

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This project was supported by the Department of Science and Technology grant no. DST-EMR: EMR/2017/001637 Department of Science and Technology, Ministry of Science and Technology, India and Department of Biotechnology, Govt. of India for BIC project grant (BT/PR40161/BTIS/137/32/2021).