Over-expressed polo-like kinases 1, a key regulator of cell mitosis, is associated with carcinogenesis and poor prognosis. It is very necessary to develop a reliable computational affinity prediction protocol targeting PLK1. In this study, the performance of different docking scoring function, free energy perturbation, MM-GBSA and QM/MM-GBSA were evaluated. The ranking capability of FEP is the best with rs = 0.854. However, the rs obtained from MM-GBSA can reach 0.767, which requires only about one-eighth of the simulation time of FEP. As for the sampling method, single long molecular dynamics (SLMD) surpass the multiple short molecular dynamics (MSMD) in ranking of the 20 congeneric compounds by about 0.1 in rs. In addition, ligands treated by QM can significantly improve the ranking performance. As for the docking scoring functions, a force field-based scoring function is more suitable for ranking congeneric compounds.

•C2 pocket of Vif was found which is suit for developing small molecular inhibitors.•FBVS was conducted against C2 pocket, and a series of fragments were obtained.•Zif-15 shows potent activity in inhibiting Vif-mediated A3G degradation.The crystal structure of viral infectivity factor (Vif) was reported recently, which makes it possible to design new inhibitors against Vif by structure-based drug design. Through analysis of the protein surface of Vif, the C2 pocket located in the N-terminal was found, which is suit for developing small molecular inhibitors. Then, in our article, fragment-based virtual screening (FBVS) was conducted and a series of fragments was obtained, among which, Zif-1 bearing indole scaffold and pyridine ring can form H-bonds with Tyr148 and Ile155. Subsequently, 19 derivatives of Zif-1 were synthesized. Through the immune-fluorescence staining and Western blot assays, Zif-15 shows potent activity in inhibiting Vif-mediated A3G degradation. Further docking experiment shows that Zif-15 form H-bond interactions with residues His139, Tyr148 and Ile155. Therefore, Zif-15 is a promising lead compound against Vif that can be used to treat AIDS.FBVS was conducted against the C2 pocket of Vif, and Zif-1 was selected for further optimization. Through the immune-fluorescence staining and western blot assays, Zif-15 shows potent activity in inhibiting Vif-mediated A3G degradation.Download high-res image (95KB)Download full-size image

•A more potent Vif antagonist 12c was obtained through the optimizations of RN-18.•12c protected APOBEC3G from degradation by inhibiting Vif function.•The glycine prodrug 13a showed an obviously improved drug-like property than 12c.Viral infectivity factor (Vif) is protective against APOBEC3G (A3G)-mediated viral cDNA hypermutations, and development of molecules that inhibit Vif mediated A3G degradation is a novel strategy for blocking HIV-1 replication. Through optimizations of the central ring of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), we found a potent compound 12c with EC50 value of 1.54 μM, enhancing the antiviral activity more than 150-fold compared with RN-18 in nonpermissive H9 cells. 12c protected A3G from degradation by inhibiting Vif function. Besides, 12c suppressed different HIV-1 clinical strains (HIV-1KM018, HIV-1TC-1 and HIV-1WAN) and drug-resistant strains (NRTI, NNRTI, PI, and FI) with relatively high activities. Amidation of 12c with glycine gave a prodrug 13a, improving the water solubility about 2600-fold compared with 12c. Moreover, 13a inhibited the virus replication efficiently with an EC50 value of 0.228 μM. These results suggested that the prodrug 13a is a promising candidate agent for the treatment of AIDS.Download high-res image (216KB)Download full-size image

•We have found a novel scaffold with better potency as antitumor agents.•Target compound 35 could arrest G0/G1 cell-cycle and induce apoptosis of SW620 cells in a dose-dependent manner.•35 blocked MCF-7 cancer cell migration with low toxicity to normal LO2 cells.•35 inhibited tumor growth by 52.96% at 80 mg/kg/48 h for 20 days.In this study, a series of novel molecules containing chromeno [3,4-d] imidazol-4(1H)-one was synthesized and their biological activities were evaluated. Among them, compound 35 showed a dramatic anticancer activity against HCT116 and MCF-7, and the flow cytometry assays demonstrated that it could arrest G0/G1 cell-cycle and induce apoptosis of SW620 cells in a dose-dependent manner. Besides, it also blocked MCF-7 cancer cell migration. Moreover, it inhibited tumor growth in HCT116 subcutaneously implanted xenografted mice. Taken together, compound 35 may be a promising candidate for anti-cancer agent as well as metastatic one.

In this research, a series of 4-(1,2,3-triazol-1-yl)coumarin conjugates were synthesized and their anticancer activities were evaluated in vitro against three human cancer cell lines, including human breast carcinoma MCF-7 cell, colon carcinoma SW480 cell and lung carcinoma A549 cell. To increase the biological potency, structural optimization campaign was conducted focusing on the C-4 position of 1,2,3-triazole and the C-6, C-7 positions of coumarin. In addition, to further evaluate the role of 1,2,3-triazole and coumarin for antiproliferative activity, 9 compounds possessing 4-(piperazin-1-yl)coumarin framework and 3 derivatives baring quinoline core were also synthesized. By MTT assay in vitro, most of the compounds display attractive antitumor activities, especially 23. Further flow cytometry assays demonstrate that compound 23 exerts the antiproliferative role through arresting G2/M cell-cycle and inducing apoptosis.

PI3Kα (phosphatidylinositol-3-kinase α) and mTOR (the mammalian target of rapamycin) have been treated as anticancer targets in recent years. Since isoform-specific inhibitors may be tolerated at doses that result in complete inhibition without generating side effects, a selectivity study is valuable. In this paper, 3D-QSAR CoMFA models on 72 selective inhibitors were established using the conformations docked to the homology models, which show satisfactory linear correlations (PI3Kα: r2 = 0.839, rpred2 = 0.743; mTOR: r2 = 0.813, rpred2 = 0.932). The results reveal that the electrostatic field in the hinge region, the steric field and electrostatic field in the solvent accessible region and the affinity subpocket have critical impacts on selectivity. To validate the 3D-QSAR models and further explore the origin of the selectivity at the amino acid residue level, molecular dynamics simulations followed by MM/GBSA binding free energy decomposition were conducted, and the result shows that R770, S773, Q859 of PI3Kα and E2190, C2243 of mTOR are the significant residues, which is in accordance with the 3D-contour maps of CoMFA. By combination of comparative analysis of binding sites, building of 3D-QSAR models and MM/GBSA binding free energy decomposition, those residues which can introduce ligand selectivity were discovered and further validated.

5, 5-disubstituted aminohydantoins have been recently reported as potent and selective human β-secretase (BACE-1) inhibitors. Self-Organizing Molecular Field Analysis (SOMFA) is used to study the correlation between the molecular properties and biological activities of the 5, 5-disubstituted aminohydantoins inhibitors. Four different alignments and two charge-assigning methods were investigated. The model derived from the superposition of docked conformation with AM1 charge showed satisfied predictive ability, which has good non-cross-validated r2 (0.842), cross-validated q2 (0.792), F-test value (254.75) and satisfied predictive ability r2pred (0.721). Analysis of SOMFA model may provide some useful information in the design of BACE-1 inhibitors with better spectrum of activity.Research highlights► 3D-QSAR SOMFA model of 5, 5-disubstituted aminohydantoin derivatives for BACE-1 nonpeptide inhibitors was constructed. ► The statistical results have good non-cross-validated r2 (0.842), cross-validated q2 (0.792), F-test value (254.75) and satisfied predictive ability r2pred (0.721). ► Four different alignments and two charge-assigning methods were investigated. Among the four alignment method, superposition of docked conformations give the best results. Further alignment of docked conformation by aminohydantoin scaffold may slightly degenerate the SOMFA model. ► If the active ligand conformation was available, construction of other derivatives by using the ligand as template is more appropriate.

Two series of 3-aminopyrazole compounds including 24 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles and 16 pyrazolo[3,4-b]pyridines were synthesized and evaluated against HCT116, A549, and A2780 tumor cell lines. Among them, three compounds were found to have the ideal anti-proliferative activities in vitro. Docking experiments showed that the novel pyrazolo[3,4-b]pyridines share the similar interaction mode with Aurora-A kinase as PHA739358.Pyrazolo[3,4-b]pyridines represented as a novel class of compounds to inhibit the Aurora-A’s activity were synthesized and evaluated.