基于分子对接和QSAR方法预测B-Raf II型抑制剂活性

B-Raf激酶在促分裂素原活化蛋白激酶(MAPK)信号转导通路中起着重要作用,已被确定为癌症治疗非常有吸引力的靶标.新型高效B-Raf抑制剂的开发成为癌症治疗的一个热门研究领域.本文以结构多样的B-Raf II型抑制剂为研究对象,联合应用分子对接和定量构效关系(QSAR)模型研究其定量构效关系去探讨抑制活性的起源.两个主题作为研究重点:生物活性构象和描述符.首先对分子对接方法(Glide、Gold、LigandFit、Cdocker和Libdock)进行准确性评价,后将研究的对象分子对接到B-Raf活性位点并获得生物活性构象.基于准确的对接结果,计算得到16个打分评价函数和21个能量描述符,以此构建定量构效关系模型. QSAR结果表明模型具有高度精确的拟合和强的预测能力(模型M1: r² = 0.852, r_(CV)² = 0.790, r_pre² = 0.864;模型M2: r² = 0.738, r_(CV)² = 0.812, r_pre² = 0.8605).同时探讨了对抑制活性有重要影响的描述符,结果表明打分评价函数(G_Score, -ECD, Dock_Score, PMF)与能量描述符(S(hb_ext), DE(int), Emodel)对抑制活性影响非常大.通过虚拟筛选和QSAR模型理论预测,一些新的具有潜在抑制活性的化合物作为B-Raf II型抑制剂被获得.上述信息对于进一步设计新颖高效的B-Raf II型抑制剂提供了有用的指导.     

Molecular beam epitaxy growth of monolayer hexagonal MnTe2 on Si(111) substrate

Monolayer MnTe₂ stabilized as 1T structure has been theoretically predicted to be a two-dimensional (2D) ferromagnetic metal and can be tuned via strain engineering. There is no naturally van der Waals (vdW) layered MnTe₂ bulk, leaving mechanical exfoliation impossible to prepare monolayer MnTe₂. Herein, by means of molecular beam epitaxy (MBE), we successfully prepared monolayer hexagonal MnTe₂ on Si(111) under Te rich condition. Sharp reflection high-energy electron diffraction (RHEED) and low-energy electron diffraction (LEED) patterns suggest the monolayer is atomically flat without surface reconstruction. The valence state of Mn⁴⁺ and the atom ratio of ([Te]:[Mn]) further confirm the MnTe₂ compound. Scanning tunneling spectroscopy (STS) shows the hexagonal MnTe₂ monolayer is a semiconductor with a large bandgap of ~2.78 eV. The valence-band maximum (VBM) locates at the Γ point, as illustrated by angle-resolved photoemission spectroscopy (ARPES), below which three hole-type bands with parabolic dispersion can be identified. The successful synthesis of monolayer MnTe₂ film provides a new platform to investigate the 2D magnetism.     

Protein Flexibility and Multiple Docking in Ligand Docking and Virtual Screening to the BRAF (Type Ⅰ1/2) Inhibitors

BRAF has been recognized as a promising target for cancer therapy. A number of crystal structures have been published. Molecular docking is one of the most effective techniques in the field of computer-aided drug design(CADD). Appropriate protein conformation and docking method are essential for the successful virtual screening experiments. One approach considering protein flexibility and multiple docking methods was proposed in this study. Six DFG-in/αC-helix-out crystal structures of BRAF, three docking programs(Glide, GOLD and Ligand Fit) and 12 scoring functions were applied for the best combination by judging from the results of pose prediction and retrospective virtual screening(VS). The most accurate results(mean RMSD of about 0.6 ?) of pose prediction were obtained with two complex structures(PDB: 3 C4 C and 3 SKC) using Glide SP. From the retrospective VS, the most active compounds were identified by using the complex structure of 3 SKC, indicated by a ROC/AUC score of 0.998 and an EF of 20.6 at 5% of the database screen with Glide-SP. On the whole, PDB 3 SKC could achieve a higher rate of correct reproduction, a better enrichment and more diverse compounds. A comparison of 3 SKC and the other X-ray crystal structures led to a rationale for the docking results. PDB 3 SKC could achieve a broad range of sulfonamide substitutions through an expanded hydrophobic pocket formed by a further shift of the αC-helix. Our study emphasized the necessity and significance of protein flexibility and scoring functions in both ligand docking and virtual screening.     

金属有机框架材料吸附性能应用的研究

金属有机框架材料(MOFs)是一种多孔聚合物材料,其相关研究近年来取得迅速发展。MOFs是以金属离子为中心,桥连的有机配体作为支撑经延伸形成的一类具有周期性网络结构的晶态多孔材料[1]。由于其较强的功能性、较高的比表面积、超高的孔隙率以及可调控的孔道结构[2],MOFs在储气、分离、催化、载药和光学等领域受到了极大的重视,并具有广泛的应用前景。本文从MOFs材料的结构设计出发,介绍近几年MOFs材料在能源气体(H2、CH4)的储存,H2S、CO2、有机气体分子的捕集以及医学领域(对于一些药物的吸附装载)的研究进展,并对MOFs材料在应用上存在的问题进行了阐述,对其未来的发展趋势作出展望。     

分子动力学模拟研究Fedratinib-JAK2/JAK3选择性

通过动力学模拟获得JAK2高选择性抑制剂Fedratinib在JAK2和JAK3激酶中的结合构象,结合自由能的计算结果表明Fedratinib在JAK2中更稳定.将能量分解到结合位点氨基酸,分析发现当分子在JAK2中占据P-loop区的疏水口袋,并与附近Arg980和Asp994等氨基酸形成氢键时,可以增加相对于JAK2的选择性.