分子动力学模拟揭示了对低氧瘤微环境中碳酸酶XII抑制剂的异酶选择性的结构洞察力
Venkatesan Saravanan1, Sathiya Priya Palani1, Bharath Kumar Chagaleti1
1Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, 603203, India.
Biochemical and biophysical research communications
|February 18, 2025
概括
化合物V35可以选择性地抑制碳酸无水酶IX和XII,这是癌症治疗中的关键标. 这种新型抑制剂表现出高结合稳定性和选择性,为癌症治疗提供了一个有前途的治疗候选者.
科学领域:
- 生物化学和分子生物学
- 药用化学 医学化学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 人类碳酸酶 (CA) 异酶IX和XII在癌症中过度表达,导致瘤微环境的酸化和进展.
- 这些异酶是开发新型抗癌策略的关键治疗点.
研究的目的:
- 确定和描述一种新型的碳酸无水酶IX和XII的选择性抑制剂.
- 为了研究已识别的化合物的异酶选择性和结合稳定性的分子基础.
主要方法:
- 在CA异酶中保存区域的计算分析.
- 在低氧条件下进行分子对接和分子动力学 (MD) 模拟 (500 ns).
- 有约束力的自由能量计算 (MMGBSA) 和密度函数理论 (DFT) 分析.
主要成果:
- 化合物V35 (ZINC09419065) 被确定为具有增强结合稳定性的CA IX和CA XII选择性抑制剂.
- 在CA XII中,V35与Zn形成了一个稳定的金属离子协调复合体,类似于标准抑制剂.
- MD模拟和MMGBSA计算证实了V35与CA XII的高结合稳定性和有利的结合自由能量.
结论:
- 化合物V35对CA XII比CA I具有显著的异酶选择性,这归因于特定的相互作用.
- 基功能组和HIS64运动有助于V35在CA XII.内的稳定相互作用.
- 通过抑制CA IX和XII,V35代表了开发向癌症治疗的有希望的化合物.
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