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Research Articles

An integrated computational approach to infer therapeutic targets from Campylobacter concisus and peptidomimetic based inhibition of its pyrimidine metabolism pathway

, , , , , , & ORCID Icon show all
Pages 13127-13137 | Received 27 Sep 2022, Accepted 13 Jan 2023, Published online: 31 Mar 2023
 

Abstract

Campylobacter concisus is a commensal of the human oral flora that has been allied with persistent diarrhea and inflammatory bowel disease (IBD). In children under the age of two, Campylobacter infections are common in the developing countries and have frequently been associated with mortality. They are becoming a prevalent cause of bacterial diarrhea in early adulthood in developed countries as well. The need for identifying new therapeutic targets and drugs is crucial for curbing such infections. Therefore, we identified 18 cytoplasmic potential therapeutic candidates against the type strain of C. concisus and deoxycytidine triphosphate deaminase (dCTP deaminase), involved in pyrimidine synthesis was selected for screening of peptidomimetic inhibitors (n > 30,000 peptidomimetics) against it. To the best of our knowledge, this target has not been studied for Campylobacter spp. Three potent inhibitors of this enzyme were prioritized i.e. peptidomimetic 27, 64, and 150. Dynamics simulation of 100 ns was carried out to validate findings for top-scored inhibitors along with physiology-based pharmacokinetics to estimate behavior in human body and predict dosing parameters. This verification demonstrates a first-in-human pharmacokinetic simulation for these peptidomimetics and can help enhance confidence in these peptide-like structures. Moiety 27 (IUPAC name: 5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-{[2-(2-methoxyethyl)-1-oxo-1H,2H,3H,4H-pyrrolo[1,2-a]pyrazin-3-yl]methyl}furan-2-carboxamide), 64 (IUPAC name: 3-(2-methylpropyl)-1-{3-[5-(5-oxo-1-phenylpyrrolidin-3-yl)-1,2,4-oxadiazol-3-yl]phenyl}urea), and 150 (IUPAC name: N-(3-methoxypropyl)-1-[6-(4-methylphenyl)-4H,6H,7H-[1,2,3]triazolo[4,3-c][1,4]oxazine-3-carbonyl]piperidine-4-carboxamide) were identified as potent inhibitors of C. concisus.

Communicated by Ramaswamy H. Sarma

Acknowledgment

The authors would like to thank the Deanship of Scientific Research at Shaqra University for supporting this work.

Data availability statement

Data is derived from a source in the public domain (Genbank accession no: CP000792.2) and is incorporated into the article.

Dedication

The authors would like to dedicate this paper to Prof. Dr. Atta ur Rahman (FRS) at the occasion of celebration of his 80th birthday. He is the founding father of ‘Jamil-ur-Rahman Center for Genome Research PCMD, ICCBS, University of Karachi, Pakistan and this paper is dedicated as a token of thanks for his services to science, and particularly higher education in Pakistan.

Disclsoure statement

Authors have nothing to declare that may construe as conflict of interest.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.

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