Computational-driven discovery of AI-2 quorum sensing inhibitor targeting the 5'- methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) to combat drug-resistant Helicobacter pylori

Manish Kumar; Avinash Karkada Ashok; Thejaswi Bhat; Krishnakumar Ballamoole; Pavan Gollapalli

doi:10.1016/j.compbiomed.2024.109409

Computational-driven discovery of AI-2 quorum sensing inhibitor targeting the 5'- methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) to combat drug-resistant Helicobacter pylori

Comput Biol Med. 2024 Nov 12:184:109409. doi: 10.1016/j.compbiomed.2024.109409. Online ahead of print.

Authors

Manish Kumar¹, Avinash Karkada Ashok², Thejaswi Bhat³, Krishnakumar Ballamoole⁴, Pavan Gollapalli⁵

Affiliations

¹ Central Research Laboratory, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, 575018, Karnataka, India; Center for Bioinformatics and Biostatistics, Nitte (Deemed to be University), Mangalore, 575018, Karnataka, India.
² Department of Biotechnology, Siddaganga Institute of Technology, Tumakuru, 572103, Karnataka, India.
³ Center for Bioinformatics and Biostatistics, Nitte (Deemed to be University), Mangalore, 575018, Karnataka, India; Nitte (Deemed to be University), Division of Infectious Diseases, Nitte University Centre for Science Education and Research (NUCSER), Paneer Campus, Deralakatte, Mangaluru, Karnataka, 575018, India.
⁴ Nitte (Deemed to be University), Division of Infectious Diseases, Nitte University Centre for Science Education and Research (NUCSER), Paneer Campus, Deralakatte, Mangaluru, Karnataka, 575018, India.
⁵ Central Research Laboratory, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, 575018, Karnataka, India; Center for Bioinformatics and Biostatistics, Nitte (Deemed to be University), Mangalore, 575018, Karnataka, India. Electronic address: gollapallipavan@nitte.edu.in.

PMID: 39536388
DOI: 10.1016/j.compbiomed.2024.109409

Abstract

MTAN is an attainable therapeutic target for H. pylori because it may minimize virulence production, limit resistance, and impair quorum sensing without affecting gut flora. Here, 457 compounds with anti-H. pylori activity were methodically analyzed, revealing a diverse array of chemical classes and unique compounds. Molecular docking studies identified three potential compounds with high binding affinities, Dehydrocostus lactone, keramamine B, and ZINC00013531409, each having binding affinity of -7.9, -9.2, and -8.3 kcal/mol, respectively. Molecular dynamics simulations of the ZINC00013531409-MTAN interactions in comparison with Apo-MTAN demonstrated stability and interactions of 300 ns, with key residues involved in protein-ligand binding illuminated. Analysis of hydrogen bonds (Ile52, Met174, and Arg194) and secondary structure variations further elucidated the binding interactions and conformational changes within the complex. Binding free energy calculations shed light on the energetics and interactions governing the complex formation of the ZINC00013531409-MTAN complex. PCA elucidated the dominant modes of motion, along with FEL revealed the energetically favorable states and then DCCM shed light on the correlated motions between residues. Overall, this study offers a detailed computational evaluation of ZINC00013531409 with anti-H. pylori activity, highlighting toxicity profile, conformational stability, and binding interactions, providing a foundation for further drug development efforts toward bacterial resistance.

Keywords: Free energy calculations; H. pylori; MTAN; Molecular dynamics simulations; Principal component analysis.