Anwar Saleha, Khan Mohd Shahnawaz, Yadav Dharmendra Kumar, Shahwan Moyad, Shamsi Anas
Centre of Medical and Bio-allied Health Sciences Research, Ajman University United Arab Emirates, Ajman, UAE.
Centre For Interdisciplinary Research In Basic Sciences, Jamia Millia Islamia, New Delhi, India.
Sci Rep. 2025 May 5;15(1):15625. doi: 10.1038/s41598-025-94825-1.
Ubiquitin-specific protease 21 (USP21) is a member of the ubiquitin-specific protease subfamily of deubiquitinating enzymes implicated in tumorigenesis and could be a target for anticancer therapy. Remarkably, it has been reported that overexpression and increased activity of USP21 are observed in various types of cancer, which explains the need for its novel small-molecule inhibitors. Plant-based compounds have emerged as promising candidates for therapeutic development due to their diverse biological activities and potential to modulate key molecular targets in disease pathways. In the present study, an integrated virtual screening strategy was adopted using IMPPAT 2.0. database to identify bioactive phytoconstituents that can potentially inhibit USP21. The selected compounds were subjected to physicochemical properties and binding affinity analysis for primary screening against USP21. Pharmacokinetic analysis, PASS evaluation, and interaction studies pinpointed two bioactive phytoconstituents, Ranmogenin A and Tokorogenin, as potential candidates against USP21. Further, molecular dynamics (MD) simulations for 500 ns were performed to analyze the conformational flexibility and stability of USP21-phytoconstituent complexes. The phytoconstituents were found to form stable protein-ligand complexes with USP21 throughout the simulation time. These findings provide a basis for subsequent research on Ranmogenin A and Tokorogenin as promising leads for drug development against USP21 in cancer treatment.
泛素特异性蛋白酶21（USP21）是去泛素化酶泛素特异性蛋白酶亚家族的成员，与肿瘤发生有关，可能成为抗癌治疗的靶点。值得注意的是，已有报道称在各种类型的癌症中均观察到USP21的过表达和活性增加，这解释了对其新型小分子抑制剂的需求。基于植物的化合物因其多样的生物活性以及调节疾病途径中关键分子靶点的潜力，已成为治疗开发的有前景的候选物。在本研究中，采用了一种综合虚拟筛选策略，使用IMPPAT 2.0数据库来鉴定可能抑制USP21的生物活性植物成分。对所选化合物进行物理化学性质和结合亲和力分析，以针对USP21进行初步筛选。药代动力学分析、PASS评估和相互作用研究确定了两种生物活性植物成分，即知母皂苷元A和知母皂苷元，作为针对USP21的潜在候选物。此外，进行了500纳秒的分子动力学（MD）模拟，以分析USP21 - 植物成分复合物的构象灵活性和稳定性。在整个模拟过程中，发现植物成分与USP21形成了稳定的蛋白质 - 配体复合物。这些发现为后续将知母皂苷元A和知母皂苷元作为癌症治疗中针对USP21的药物开发的有前景的先导物的研究提供了基础。
