在人工智能驱动下发现选择性TLR7对手的新型支架,并将其应用于提高mRNA翻译效率
Soyeon Yoo1, Kounghwa Youn2, Nawoon Kim3
1Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
概括
人工智能发现了新的托尔类受体7 (TLR7) 抗剂. 这些化合物在治疗自身免疫性疾病和推进mRNA疗法方面表现有前途,因为它们的疗效和选择性.
科学领域:
- 免疫学 免疫学 免疫学
- 计算化学的计算化学
- 药物发现 药物发现 药物发现
背景情况:
- 收费类受体7 (TLR7) 通过检测病毒RNA并触发炎症反应,在天生的免疫力中起着至关重要的作用.
- 调节TLR7活性为自身免疫性疾病和病毒感染提供治疗潜力,但有效的抗体很少.
- 现有研究强调需要新型TLR7抗剂支架来补充TLR7抗剂的发展.
研究的目的:
- 为了利用人工智能发现新型化学支架的收费类受体7 (TLR7) 抗剂.
- 为了确定潜在的治疗应用,强效和选择性TLR7抗剂.
- 探索已识别的TLR7抗剂在提高mRNA翻译效率方面的实用性.
主要方法:
- 利用MotifGen进行潜在的TLR7结合化合物的大规模虚拟选.
- 采用联结对接模拟来优先考虑和缩小候选分子.
- 基于高对接分数,结构多样性和体外验证的选择化合物.
主要成果:
- 确定了两种新的TLR7抗体:8-Methoxy-N-[(2,4,5,6-tetrahydro-2-methyl-3-cyclopentapyrazol) methyl]-5-quinoline和N-ethyl-2-[(5-fluoro-2,6-dimethyl-4-pyrimidinyl) amino]-N-(phenylmethyl) 乙胺.
- 这两种化合物都显示出较低的IC50值,对TLR7比TLR8和TLR9具有较高的选择性,以及较低的细胞毒性.
- 鉴定的抗剂显示出提高mRNA翻译效率的潜力.
结论:
- 该研究使用人工智能驱动的方法成功识别了新的TLR7抗剂.
- 这些化合物代表了治疗TLR7介导的自身免疫性疾病的有希望的候选者.
- 这些发现表明,这些对抗剂在推进基于mRNA的治疗中具有潜在的应用.
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