新型蝶啶酮类PLK1抑制剂的虚拟筛选

Virtual Screening of Novel Pteridone PLK1 Inhibitors

Polo样激酶1(PLK1)是治疗多种癌症的一个靶点,蝶啶酮衍生物作为PLK1抑制剂具有显著的生物活性。为了更好理解PLK1抑制剂的药效特征并筛选出具有新骨架的苗头化合物,对新型三/四唑蝶啶酮衍生物进行了系统的分子模拟,主要包括分子对接、药效团模型构建、虚拟筛选和分子动力学模拟。分子对接结果表明,关键氨基酸残基C67、A80、K82、L130、C133、F183可以通过疏水作用、氢键或π-π堆积作用与三/四唑蝶啶酮衍生物相互作用。通过构建的药效团模型,结合分子对接和药代动力学ADME预测,虚拟筛选得到了3个潜在化合物(VS01、VS02和VS03)。分子动力学模拟结果表明,VS02和VS03不仅能与PLK1稳定结合,而且结合自由能优于已报道活性最高的化合物27。为新型PLK1抑制剂的筛选和开发提供了有效信息和理论参考。

Polo-like kinase 1(PLK1)is a target for the treatment of various cancers,and pteridone derivatives have significant biological activities as PLK1 inhibitors.To better understand the pharmacodynamic characteristics of PLK1 inhibitors and screen hit compounds with new skeletons,a systematic molecular simulation of novel triazole and tetrazolium pteridone derivatives was carried out in this study,including molecular docking,construction of pharmacophore model,virtual screening,and molecular dynamics simulation.The results of molecular docking show that the key amino acid residues C67,A80,K82,L130,C133,and F183 can interact with triazole and tetrazolium pteridone derivatives through hydrophobic interaction,hydrogen bonding orπ-πstacking interaction.Three potential compounds(VS01,VS02,and VS03)are obtained by virtual screening based on the pharmacophore model,molecular docking,and pharmacokinetic ADME prediction.The molecular dynamics simulation results show that compounds VS02 and VS03 can not only bind with PLK1 stably,but also their binding free energies are better than that of the reported compound 27 with the highest activity.The results of this study can provide effective information and theoretical reference for the screening and development of novel PLK1 inhibitors.