弯曲杆菌是人类口腔菌群的共生菌,与持续性腹泻和炎症性肠病(IBD)有关。在两岁以下的儿童中,弯曲杆菌感染在发展中国家很常见,并且经常与死亡率相关。在发达国家,它们也正在成为成年早期细菌性腹泻的普遍原因。确定新的治疗靶标和药物的需要对于遏制此类感染至关重要。因此,我们确定了18种细胞质潜在的治疗候选株针对C.concisus和脱氧胞苷三磷酸脱氨酶(dCTP脱氨酶),选择参与嘧啶合成的肽模拟物抑制剂(n>30,000个肽模拟物)的筛选。据我们所知,尚未对弯曲杆菌进行研究。该酶的三种有效抑制剂被优先考虑,即肽模拟物27、64和150。进行了100ns的动力学模拟,以验证得分最高的抑制剂以及基于生理学的药代动力学的发现,以估计人体行为并预测给药参数。该验证证明了这些肽模拟物的首次人体药代动力学模拟,并且可以帮助增强对这些肽样结构的信心。部分27(IUPAC名称:5-[(3,5-二甲基-1H-吡唑-1-基)甲基]-N-{[2-(2-甲氧基乙基)-1-氧代-1H,2H,3H,4H-吡咯并[1,2-a]吡嗪-3-基]甲基}呋喃-2-甲酰胺),64(IUPAC名称:3-(2-甲基丙基)-1-{3-[5-(5-氧代-1-苯基吡咯烷-3-基)-1,2,4-恶二唑-3-基]苯基}脲),和150(IUPAC名称:N-(3-甲氧基丙基)-1-[6-(4-甲基苯基)-4H,6H,7H-[1,2,3]三唑并[4,3-c][1,4]恶嗪-3-羰基]哌啶-4-甲酰胺)被鉴定为C.concisus的有效抑制剂。由RamaswamyH.Sarma沟通。
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.