Sulaimani Md Nayab, Ahmed Shazia, Anjum Farah, Mohammad Taj, Shamsi Anas, Dohare Ravins, Hassan Md Imtaiyaz
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.
Department of Computer Science, Jamia Millia Islamia, New Delhi, India.
PLoS One. 2025 Jan 24;20(1):e0311954. doi: 10.1371/journal.pone.0311954. eCollection 2025.
Mitogen-activated protein kinase 1 (MAPK1) is a serine/threonine kinase that plays a crucial role in the MAP kinase signaling transduction pathway. This pathway plays a crucial role in various cellular processes, including cell proliferation, differentiation, adhesion, migration, and survival. Besides, many chemotherapeutic drugs targeting the MAPK pathway are used in clinical practice, and novel inhibitors of MAPK1 with improved specificity and efficacy are required. Hence, targeting MAPK1 can be crucial to control metastasis in cancer therapeutics. In this study, we utilized a structure-guided virtual screening approach to screen a library of thousands of natural compounds from the ZINC database. The Lipinski rule of five (RO5) was used as a criterion for the primary selection of natural compounds. The screened compounds were prioritized based on their binding affinity, docking scores, and specificity towards the kinase domain of MAPK1 during the molecular docking process. Subsequently, the selected hits underwent rigorous screening that included the identification of potential pan-assay interference compounds (PAINS), ADMET evaluation, and prediction of pharmacological activities using PASS analysis. Afterwards, we performed a comprehensive interaction analysis to explore the binding prototypes of the screened molecules with the key residues within the MAPK1 kinase domain. Finally, selected molecules underwent extensive all-atom molecular dynamics (MD) simulations for a time duration of 200 nanoseconds. The study pinpointed three natural compounds with ZINC database IDs ZINC0209285, ZINC02130647, and ZINC02133691 as potential inhibitors of MAPK1. The study highlights that these compounds could be explored further in preclinical and clinical investigations to develop anticancer therapeutics.
丝裂原活化蛋白激酶1（MAPK1）是一种丝氨酸/苏氨酸激酶，在MAP激酶信号转导通路中起关键作用。该通路在多种细胞过程中起关键作用，包括细胞增殖、分化、黏附、迁移和存活。此外，许多靶向MAPK通路的化疗药物已应用于临床实践，因此需要具有更高特异性和疗效的新型MAPK1抑制剂。因此，靶向MAPK1对于癌症治疗中控制转移可能至关重要。在本研究中，我们采用基于结构的虚拟筛选方法，从ZINC数据库中筛选了数千种天然化合物库。Lipinski五规则（RO5）被用作天然化合物初步筛选的标准。在分子对接过程中，根据筛选出的化合物对MAPK1激酶结构域的结合亲和力、对接分数和特异性进行排序。随后，对选定的命中化合物进行严格筛选，包括潜在的泛分析干扰化合物（PAINS）鉴定、ADMET评估以及使用PASS分析预测药理活性。之后，我们进行了全面的相互作用分析，以探索筛选出的分子与MAPK1激酶结构域内关键残基的结合模式。最后，对选定的分子进行了长达200纳秒的广泛全原子分子动力学（MD）模拟。该研究确定了三种ZINC数据库ID分别为ZINC0209285、ZINC02130647和ZINC02133691的天然化合物作为MAPK1的潜在抑制剂。该研究强调，这些化合物可在临床前和临床研究中进一步探索，以开发抗癌治疗药物。
