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

• Published in: Journal of biomolecular structure & dynamics 2023-12, Vol.41 (22), p.13127-13137
• Main Authors: Khan, Kanwal, Jalal, Khurshid, Alam, Yasir, Alotaibi, Ghallab, Al Mouslem, Abdulaziz, Uddin, Reaz, Hassan, Syed Shah, Basharat, Zarrin
• Format: Article
• Language: English
• Subjects: Campylobacter concisus; docking; drug design; peptidomimetics; subtractive genomics; virtual screening
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2023.2191148

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