Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China.
Phys Chem Chem Phys. 2024 Mar 13;26(11):8767-8774. doi: 10.1039/d3cp05846h.
Carbonic anhydrase IX (CA IX) is a subtype of the human carbonic anhydrase (CA) family and exhibits high expression in various solid tumors, rendering it a promising target for tumor therapy. Currently, marketed carbonic anhydrase inhibitors (CAIs) are primarily composed of sulfonamides derivatives, which may have impeded their potential for further expansion. Therefore, we have developed a structure-based virtual screening approach to explore novel CAIs exhibiting distinctive structures and anti-tumor potential in the FDA database. experiments demonstrated that 3-pyridinemethanol (0.42 μM), procodazole (8.35 μM) and pamidronic acid (8.51 μM) exhibited inhibitory effects on CA IX activity. The binding stability and interaction mode between the CA IX and the hit compounds are further investigated through molecular dynamics simulations and binding free energy calculations. Furthermore, the ADME/Tox prediction results indicated that these compounds exhibited favorable pharmacological properties and minimal toxic side effects. Our study successfully applied computational strategies to discover three non-sulfonamide inhibitors of carbonic anhydrase IX (CA IX) that demonstrate inhibitory activity . These findings have significant implications for the development of CA IX inhibitors and anti-tumor drugs, contributing to their progress in the field.
碳酸酐酶 9（CA9）是人类碳酸酐酶（CA）家族的一个亚型，在各种实体瘤中高表达，使其成为肿瘤治疗的有前途的靶点。目前，市售的碳酸酐酶抑制剂（CAIs）主要由磺胺类衍生物组成，这可能阻碍了它们进一步扩展的潜力。因此，我们开发了一种基于结构的虚拟筛选方法，以探索在 FDA 数据库中具有独特结构和抗肿瘤潜力的新型 CAIs。实验表明，3-吡啶甲醇（0.42μM）、普罗多唑（8.35μM）和帕米膦酸（8.51μM）对 CA9 活性具有抑制作用。通过分子动力学模拟和结合自由能计算进一步研究了 CA9 与命中化合物之间的结合稳定性和相互作用模式。此外，ADME/Tox 预测结果表明，这些化合物具有良好的药理性质和最小的毒副作用。我们的研究成功地应用计算策略发现了三种非磺胺类碳酸酐酶 9（CA9）抑制剂，它们具有抑制活性。这些发现对 CA9 抑制剂和抗肿瘤药物的开发具有重要意义，为该领域的发展做出了贡献。
