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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Virtual screening, molecular dynamics, and binding free energy calculations on human carbonic anhydrase IX catalytic domain for deciphering potential leads
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Virtual screening, molecular dynamics, and binding free energy calculations on human carbonic anhydrase IX catalytic domain for deciphering potential leads

机译：用于解吸潜在引线的人碳酸酐酶IX催化结构域的虚拟筛选，分子动力学和结合自由能量计算

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摘要

Carbonic anhydrase IX is a tumor-associated membrane-bound metallo-enzyme which catalyzes the reversible hydration of carbon dioxide (CO2) to bicarbonate (HCO3-) and proton (H+) ions. It is a hypoxia-inducible enzyme and plays a critical role in tumor pH homeostasis favoring tumor cell invasiveness and drug resistance. Over expression of CAIX is documented in cancers of breast, lung, kidney, colon/rectum, etc. Chemical inhibition of CAIX activity has proven to be an effective therapeutic modality towards targeting cancer. Hence, in this study, we intend to identify potential molecules from NCI (National Cancer Institute) and Maybridge databases implementing high-throughput virtual screening. CAIX co-crystallized with acetazolamide (a known inhibitor of CAIX) (PDB ID: 3IAI) was used for reference-guided docking protocol. The potential inhibitors among the coupled data sets were finalized based on Glide docking score, Prime/MMGBSA scoring, significant intermolecular interactions, ADMET (absorption, distribution, metabolism and excretion, toxicity) prediction and stability of complex formation, molecular dynamics simulation, and comparative analysis. By this study, we propose NSC_93618, NSC_170253, NSC_93618, JFD03677, SEW06488, and BTB09372 to be highly significant, as all these compounds were found to qualify as potential leads surpassing all the stringent filtering process. However, NSC_93618 was found to be the most potential, as it featured with higher complex stability with strong bonded interactions, binding affinity synonymous to acetazolamide. Hence, these proposed compounds shall prove to be effective in targeting CAIX towards modulating carcinogenesis.
机译：碳酸酐酶IX是一种肿瘤相关膜结合的金属酶，其催化二氧化碳（CO 2）的可逆水合碳酸氢盐（HCO3-）和质子（H +）离子。它是一种缺氧诱导酶，并在肿瘤pH稳态中发挥关键作用，青睐肿瘤细胞侵袭性和耐药性。 CAIX的表达被记录在乳腺癌，肺，肾，结肠/直肠癌的癌症中。CAIX活性的化学抑制已被证明是针对靶向癌症的有效治疗方式。因此，在这项研究中，我们打算识别来自NCI（国家癌症学院）的潜在分子和实现高吞吐量虚拟筛选的Maybridge数据库。用乙酰唑胺（CaIX的已知抑制剂）共结晶（PDB ID：3iai），用于参考引导对接方案。耦合数据集中的潜在抑制剂是基于Glide对接评分，Prime / MMGBSA评分，显着的分子间相互作用，探测器（吸收，分布，代谢和排泄，毒性）预测和复杂形成，分子动力学模拟和比较的稳定性分析。通过本研究，我们提出了NSC_93618，NSC_170253，NSC_93618，JFD03677，SEF06488和BTB09372非常重要，因为所有这些化合物都被发现有资格，因为潜在的导致超过所有严格的过滤过程。然而，发现NSC_93618是最潜力的，因为它具有较高的复杂稳定性，具有强粘合的相互作用，将亲和力与乙酰唑胺的结合同义。因此，这些所提出的化合物应证明是有效靶向CAIX调节致癌作用。

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