Agarwal Manisha, Rajkhowa Sanchaita, Zaki Magdi E A, Sinha Subrata
Centre for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, Assam, 786004, India.
Centre for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, Assam, 786004, India.
Comput Biol Med. 2025 Sep;196(Pt B):110769. doi: 10.1016/j.compbiomed.2025.110769. Epub 2025 Jul 16.
Post-translational modifications fine-tune protein function and regulate key signalling pathways in eukaryotic cells. ADP-ribosylation, which is catalyzed by the poly(ADP‒ribose) polymerase (PARP) family of enzymes, governs processes such as transcription, DNA repair, and inflammation. PARP14, a mono-ADP-ribosyltransferase, has emerged as a key player in cancer, with its overexpression linked to aggressive B-cell lymphomas and metastatic prostate cancer, positioning it as a promising therapeutic target. This study aimed to identify novel PARP14 inhibitors by repurposing existing compounds for anticancer applications via a ligand-based computational strategy. Using advanced techniques for 3D quantitative structure-activity relationship and pharmacophore modeling, we created a reliable pharmacophore model (Hypo1) via a varied dataset of 60 confirmed PARP14 inhibitors for accuracy. The evaluation of more than 71,540 compounds from the DrugBank and IBScreen libraries through virtual screening, followed by molecular docking studies, resulted in the assessment of these compounds against Veber's and Lipinski's drug-like criteria and optimal ADMET properties. This process identified four promising candidates: Furosemide, Vilazodone, STOCK1N-42868, and STOCK1N-92908. Molecular dynamics simulations and MM-PBSA analysis provided additional evidence of the stability and positive interactions of these ligands with PARP14. Furosemide and Vilazodone exhibited significant binding affinity and anticancer properties, whereas STOCK1N-42868 emerged as a novel candidate with promising in silico results. These findings suggest that Furosemide and Vilazodone could be effectively repurposed as PARP14 inhibitors, offering a strategic approach to enhance the efficacy of cancer treatment, whereas STOCK1N-42868 represents an exciting avenue for further research. This study emphasizes the possible applications of computational methods for finding new drugs and stresses the importance of pre-clinical research to examine how these inhibitors work in cancer treatment.
翻译后修饰可微调蛋白质功能并调节真核细胞中的关键信号通路。由聚（ADP - 核糖）聚合酶（PARP）家族酶催化的ADP - 核糖基化作用，调控转录、DNA修复和炎症等过程。PARP14是一种单ADP - 核糖基转移酶，已成为癌症中的关键角色，其过表达与侵袭性B细胞淋巴瘤和转移性前列腺癌相关，使其成为一个有前景的治疗靶点。本研究旨在通过基于配体的计算策略，将现有化合物重新用于抗癌应用，以鉴定新型PARP14抑制剂。利用先进的3D定量构效关系和药效团建模技术，我们通过60种已确认的PARP14抑制剂的多样化数据集创建了一个可靠的药效团模型（Hypo1），以确保准确性。通过虚拟筛选对DrugBank和IBScreen库中的71,540多种化合物进行评估，随后进行分子对接研究，根据Veber和Lipinski的类药标准以及最佳ADMET性质对这些化合物进行评估。这一过程确定了四个有前景的候选物：呋塞米、维拉唑酮、STOCK1N - 42868和STOCK1N - 92908。分子动力学模拟和MM - PBSA分析为这些配体与PARP14的稳定性和正向相互作用提供了额外证据。呋塞米和维拉唑酮表现出显著的结合亲和力和抗癌特性，而STOCK1N - 42868作为一个具有前景的计算机模拟结果的新型候选物出现。这些发现表明，呋塞米和维拉唑酮可以有效地重新用作PARP14抑制剂，为提高癌症治疗疗效提供了一种策略性方法，而STOCK1N - 42868代表了一个令人兴奋的进一步研究途径。本研究强调了计算方法在寻找新药方面的可能应用，并强调了临床前研究对于检验这些抑制剂在癌症治疗中如何发挥作用的重要性。
