Almansour Nahlah Makki
Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin 31991, Saudi Arabia.
Int J Mol Sci. 2025 Aug 30;26(17):8465. doi: 10.3390/ijms26178465.
Carbonic anhydrase IX (CA IX) is a transmembrane metalloenzyme that is increased in tumor cells under hypoxia and plays an important role in solid tumor acidification. It is a marker of tumor hypoxia and a prognostic factor in human malignancies. Given the critical role of CA IX and their over expression in many cancer tissues, they have emerged as a promising target for developing novel anticancer therapeutics. In this study we designed a pharmacophore model based on known inhibitors to screen small compound libraries to discover potential inhibitors of CA IX. Molecular docking experiments discovered that four compounds ZINC613262012, ZINC427910039, ZINC616453231, and DB00482 exhibited a strong binding affinity towards CA IX, mimicking the interaction pattern similar to native inhibitors. Molecular dynamics simulations and an MM-PBSA analysis revealed ZINC613262012, ZINC427910039, and DB00482 as the most potential and stable inhibitors with the binding free energies -10.92, -18.77, and -12.29 kcal/mol, respectively. In addition, DFT-based analyses supported their favorable electronic properties, further validating their potential as CA IX inhibitors. These three hits demonstrated a greater stability and compactness relative to the known inhibitors, suggesting these might be used CA IX inhibitors to treat tumors.
碳酸酐酶IX（CA IX）是一种跨膜金属酶，在缺氧条件下肿瘤细胞中表达增加，在实体瘤酸化中起重要作用。它是肿瘤缺氧的标志物，也是人类恶性肿瘤的预后因素。鉴于CA IX的关键作用及其在许多癌症组织中的过表达，它们已成为开发新型抗癌疗法的有希望的靶点。在本研究中，我们基于已知抑制剂设计了一个药效团模型，以筛选小分子化合物库，发现CA IX的潜在抑制剂。分子对接实验发现，四种化合物ZINC613262012、ZINC427910039、ZINC616453231和DB00482对CA IX表现出强烈的结合亲和力，模拟了与天然抑制剂相似的相互作用模式。分子动力学模拟和MM-PBSA分析表明，ZINC613262012、ZINC427910039和DB00482是最具潜力和稳定性的抑制剂，结合自由能分别为-10.92、-18.77和-12.29 kcal/mol。此外，基于密度泛函理论（DFT）的分析支持了它们良好的电子性质，进一步验证了它们作为CA IX抑制剂的潜力。相对于已知抑制剂，这三个命中化合物表现出更高的稳定性和紧凑性，表明它们可能用作CA IX抑制剂来治疗肿瘤。
