Amity Institute of Biotechnology, Amity University, Kolkata, India.
Amity Institute of Biotechnology, Amity University, Kolkata, India.
Comput Biol Med. 2024 Nov;182:109096. doi: 10.1016/j.compbiomed.2024.109096. Epub 2024 Sep 12.
Pancreatic cancer, the 12th-most common cancer, globally, is highly challenging to treat due to its complex epigenetic, metabolic, and genomic characteristics. In pancreatic ductal adenocarcinoma, USP21 acts as an oncogene by stabilizing the long isoform of Transcription Factor 7, thereby activating the Wnt signaling pathway. This study aims to inhibit activation of this pathway through computer-aided drug discovery. Accordingly, four libraries of compounds were designed to target the USP21's catalytic domain (Cys221, His518, Asp534), responsible for its deubiquitinating activity.
Utilizing an array of computer-aided drug design methodologies, such as molecular docking, virtual screening, principal component analysis, molecular dynamics simulation, and dynamic cross-correlation matrix, the structural and functional characteristics of the USP21-inhibitor complex were examined. Following the evaluation of the binding affinities, 20 potential ligands were selected, and the best ligand was subjected to additional molecular dynamics simulation study.
The results indicated that the ligand-bound USP21 exhibited reduced structural fluctuations compared to the unbound form, as evident from RMSD, RMSF, Rg, and SASA graphs. ADMET analysis of the top ligand showed promising pharmacokinetic and pharmacodynamic profiles, good bioavailability, and low toxicity. The stable conformations of the proposed drug when bound to their target cavities indicate a robust binding affinity of -9.3 kcal/mol. The drug exhibits an elevated pKi value of 6.82, a noteworthy pIC value of 5.972, and a pKd value of 6.023 proving its high affinity and inhibitory potential towards the target.
In-vitro testing of the top compound (MOLHYB-0436) could lead to its use as a potential treatment for pancreatic cancer.
胰腺癌是全球第 12 大常见癌症，由于其复杂的表观遗传、代谢和基因组特征，治疗极具挑战性。在胰腺导管腺癌中，USP21 通过稳定转录因子 7 的长异构体而起癌基因作用，从而激活 Wnt 信号通路。本研究旨在通过计算机辅助药物发现来抑制该通路的激活。为此，设计了四个化合物库来靶向 USP21 的催化结构域（Cys221、His518、Asp534），负责其去泛素化活性。
利用一系列计算机辅助药物设计方法，如分子对接、虚拟筛选、主成分分析、分子动力学模拟和动态互相关矩阵，研究了 USP21 抑制剂复合物的结构和功能特征。在评估结合亲和力后，选择了 20 个潜在配体，并对最佳配体进行了额外的分子动力学模拟研究。
结果表明，与未结合形式相比，配体结合的 USP21 表现出结构波动减小，从 RMSD、RMSF、Rg 和 SASA 图中可以看出。顶级配体的 ADMET 分析显示出有希望的药代动力学和药效学特征、良好的生物利用度和低毒性。当与目标腔结合时，所提出药物的稳定构象表明其结合亲和力为-9.3 kcal/mol。该药物表现出升高的 pKi 值为 6.82、显著的 pIC 值为 5.972 和 pKd 值为 6.023，证明其对靶标具有高亲和力和抑制潜力。
对顶级化合物（MOLHYB-0436）进行体外测试可能使其可用于治疗胰腺癌。
