通过计算加速识别P-糖蛋白抑制剂的P-糖蛋白抑制剂
bioRxiv : the preprint server for biology
|September 30, 2024
概括
针对核酸结合域的新型P-glycoprotein (P-gp) 抑制剂在逆转癌细胞多药性耐药性 (MDR) 方面表现有前途. 这些化合物是无毒的,是进一步开发的潜在候选物.
科学领域:
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
- 计算化学计算化学
背景情况:
- 过度表达P-glycoprotein (P-gp) 在癌症中驱动多药性耐药性 (MDR),限制化疗的疗效.
- 现有的P-gp抑制剂通常由于基质特性和向跨膜域而失败.
- P-gp的细胞质核酸结合域代表了一个尚未探索的治疗标.
研究的目的:
- 开发和应用一个增强的计算管道,用于识别新型P-gp抑制剂.
- 针对P-gp的细胞质核酸结合域来逆转MDR.
- 发现具有降低基质潜力的无毒P-gp抑制剂.
主要方法:
- 利用计算加速的药物发现与代分子对接对抗多个P-gp构造.
- 采用有针对性的分子动力学模拟来产生多样化的对接受体构造.
- 选定制的tanimoto化学数据集,以最大限度地提高连接物多样性.
主要成果:
- 确定了9种新的P-gp抑制剂,其成功率为13.4%.
- 在P-gp过度表达的人类癌细胞系中证明了MDR的逆转.
- 发现所有已识别的抑制剂对正常人体细胞是无毒的,其中六种不太可能是P-gp基质.
结论:
- P-gp的细胞质核酸结合域是克服MDR的可行和有前途的目标.
- 开发的计算管道有效地识别了新的MDR逆转剂.
- 新型P-gp抑制剂具有化学多样性,适用于癌症治疗中的优化.
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