通过大规模匹配分子对分析,对P-糖蛋白介导的外流进行动性建模
1Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
European journal of medicinal chemistry
|September 29, 2023
概括
了解P-glycoprotein (Pgp) 排泄是药物开发的关键. 提高被动透性提供了一种减轻Pgp介导药物耐药性和改善药物输送的策略.
科学领域:
- 药理学 药理学是指药理学的学科.
- 生物化学 生物化学
- 药物发现 药物发现 药物发现
背景情况:
- P-glycoprotein (Pgp) 流出显著影响药物ADME特性,并有助于癌症多药耐药性.
- 了解基质-Pgp相互作用对于预测和克服流出挑战至关重要.
研究的目的:
- 阐明基质特性与Pgp介导的流动之间的机械关系.
- 评估基于规则的方法和物理化学性质,以缓解流失的策略.
- 要突出被动透性在克服Pgp排泄中的作用.
主要方法:
- 动态建模分析基质-Pgp相互作用和流出机制.
- 匹配的分子对分析,以评估 efflux 的结构-活动关系.
- 对包括PROTACs在内的各种化合物类的物理化学性质分析.
主要成果:
- 动力建模弥合了极性PGP基板和疏水性结合部位之间的差距.
- 基于规则的方法 (例如,H-债券捐赠者,极地表面积) 显示出对流量缓解的局限性.
- 增加内在的被动透性是降低流出比率的关键因素.
- 与符合五项规则的化合物相比,PROTACs具有独特的物理化学特性,以逃避排泄.
结论:
- 将被动透性与特定基质-Pgp相互作用分开,对于合理的药物设计至关重要.
- 提高被动透性的策略对于减轻Pgp介导的流量至关重要.
- 需要更深入的机制理解来设计能够有效避开PGP排泄的药物.
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