Silva Ohana Leticia Tavares, Alves Monique Gabriela das Chagas Faustino, Rocha Hugo Alexandre Oliveira
Graduate Program in Biochemistry and Molecular Biology, Center of Biosciences, Federal University of Rio Grande do Norte-UFRN, Av. Sen. Salgado Filho, 3000, Natal 59078-900, Brazil.
Mar Drugs. 2024 Dec 26;23(1):6. doi: 10.3390/md23010006.
Carrageenans have demonstrated enhanced antitumor activity upon depolymerization into disaccharides. However, the pharmacological viability of these disaccharides and their mechanisms of antitumor action remains to be fully elucidated. This study aimed to employ computational tools to investigate the pharmacological properties and molecular targets pertinent to cancer of the disaccharides derived from the primary carrageenans. Analyses of pharmacological properties predicted by the pkCSM and SwissADME servers indicated that the disaccharides possess a favorable pharmacokinetic profile, although they encounter permeability challenges primarily due to their high polarity and low lipophilicity. Target prediction using SwissTarget and PPB2 identified five carbonic anhydrases, which are also targets of oncology drugs, as common targets for the disaccharides. Molecular docking performed with AutoDock Vina revealed that the binding energies of the disaccharides with carbonic anhydrases were comparable to or greater than those of existing drugs that target these lyases. Notably, six of the complexes formed exhibited interactions between the disaccharides and the zinc cofactor, which represents a primary mechanism of inhibition for these targets. Furthermore, molecular dynamics simulations conducted using GROMACS demonstrated a stable interaction between the disaccharides and carbonic anhydrases. These findings offer new insights into the pharmacological properties and mechanisms of action of carrageenan-derived disaccharides, highlighting their potential for further exploration in clinical trials and experimental studies.
角叉菜胶解聚为二糖后显示出增强的抗肿瘤活性。然而，这些二糖的药理可行性及其抗肿瘤作用机制仍有待充分阐明。本研究旨在利用计算工具研究与初级角叉菜胶衍生的二糖相关的癌症药理学特性和分子靶点。由pkCSM和SwissADME服务器预测的药理学特性分析表明，这些二糖具有良好的药代动力学特征，尽管它们主要由于高极性和低亲脂性而面临渗透性挑战。使用SwissTarget和PPB2进行的靶点预测确定了五种碳酸酐酶，它们也是肿瘤学药物的靶点，作为二糖的共同靶点。用AutoDock Vina进行的分子对接显示，二糖与碳酸酐酶的结合能与靶向这些裂解酶的现有药物相当或更高。值得注意的是，形成的六种复合物中二糖与锌辅因子之间存在相互作用，这代表了这些靶点的主要抑制机制。此外，使用GROMACS进行的分子动力学模拟表明二糖与碳酸酐酶之间存在稳定的相互作用。这些发现为角叉菜胶衍生的二糖的药理学特性和作用机制提供了新的见解，突出了它们在临床试验和实验研究中进一步探索的潜力。
