摘要：A novel type of quinazoline derivatives,which were designed by the combination of quinazoline as the back-bone and oxazole scaffold as the substituent,have been synthesized and their biological activities were evaluated for anti-proliferative activities and EGFR inhibitory *** 12b demonstrated the most potent inhibi-tory activity(IC_(50)=0.95μmol/L for EGFR),which could be optimized as a potential EGFR inhibitor in the further *** structures of the synthesized quinazoline analogs and all intermediates were comfirmed by 1H and 13C NMR,2D NMR spectra,IR spectra and MS spectra.

摘要：Polypharmacology,which focuses on designing drugs to target multiple receptors,has emerged as a new paradigm in drug *** rationally design multi-target drugs,it is fundamental to understand protein-ligand interactions on a proteome *** have developed a Proteome-wide Off-target Pipeline （POP） that integrates ligand binding site analysis,protein-ligand docking,the statistical analysis of docking scores,and electrostatic potential *** utility of POP is demonstrated by a case study,in which the molecular mechanism of anti-cancer effect of Nelfinavir is *** combining structural proteome-wide off-target identification and systems biology,it is possible for us to correlate drug perturbations with clinical outcomes.

摘要：The differential distribution between cancer cells and normal adult tissues makes survivin a very attractive cancer drug target. We have previously reported a series of novel selective survivin inhibitors with the most potent compound MX 106 reaching nanomolar activity in several cancer cell lines. Further optimization of the MX 106 scaffold leads to the discovery of more potent and more selective survivin inhibitors. Various structural modifications were synthesized and their anticancer activities were evaluated to determine the structure activity relationships for this MX 106 scaffold. In vitro anti-proliferative assays using two human melanoma cell lines showed that several new analogs have improved potency compared to MX 106. Very interestingly, these new analogs generally showed significantly higher potency against P-glycoprotein overexpressed cells compared with the corresponding parental cells, suggesting that these compounds may strongly sensitize tumors that have high expressions of the Pglycoprotein drug efflux pumps. Western blotting analysis confirmed that the new MX 106 analogs maintained their mechanism of actions by selectively suppressing survivin expression level among major inhibitors of apoptotic proteins and induced strong apoptosis in melanoma tumor cells.

摘要：The present work deals with the development of controlled release tablets of salbutamol sulphate(SS)using graft copolymers of methyl methacrylate(St-g-PMMA and Ast-g-PMMA)on starch and acetylated *** were evaluated for physical characteristics like hardness,friability,drug release,drug content and weight variations,which fulfilled all the official requirements of tablet dosage *** release rates from formulated matrix tablets were studied at SGF(pH 1.2)followed by SIF(pH 6.8).Drug release from the graft copolymer based tablets was found to be sustained upto the 14 h with>75%drug *** in-vitro release study showed that the graft copolymer based matrix formulations(F3&F4)exhibited highest correlation value(r2)for higuchi kinetic model and Korsmeyer's model with n values between 0.61 and 0.67 proved that release mechanisms were governed by both diffusion and erosion *** was no significant difference in the pharmacokinetic parameters(tmax,Cmax,AUC,Ke,and t1/2)of the graft copolymers matrices and HPMC K100M matrix tablets,indicating their comparable sustained release *** potential of graft copolymers to sustain the drug release is well supported by in-vivo pharmacokinetic studies and their adequate physicochemical properties make them promising excipients for controlled drug delivery system.

摘要：We previously demonstrated that polypod-like structured DNA, or polypodna, constructed with three or more oligodeoxynucleotides （ODNs）, is efficiently taken up by immune cells such as dendritic cells and macrophages, depending on its structural complexity. The ODNs comprising the polypodna should bend to form the polypod-like structure, and may do so by adopting either a bend- type conformation or a cross-type conformation. Here, we tried to elucidate the orientation and bending of ODNs in polypodnas using atomic force microscopy （AFM）. We designed two types of pentapodnas （i.e., a polypodna with five pods） using 60- to 88-base ODNs, which were then immobilized on DNA origami frames. AFM imaging showed that the ODNs in the pentapodna adopted bend-type conformations. Tetrapodna and hexapodna also adopted bend-type conformations when they were immobilized on frames under unconstrained conditions. These findings provide useful information toward the coherent design of, and the structure-activity relationships for, a variety of DNA nanostructures.

摘要：Fragment-based drug discovery （FBDD） has been widely applied in the research of aspartyl protease inhibitors. In the present study, we reported our work on 2-aminobenzimidazole as the original fragment, which was predicted to bind with the catalytic aspartyl dyad （Asp228 and Asp32） of D-site amyloid precursor protein cleaving enzyme 1 （BACE1）. A series of novel 2-aminobenzimidazole derivatives were designed and synthesized. The results from FRET assay revealed that three out of the 12 designed 2-aminobenzimidazoles could inhibit more than 50% of the enzymatic potency of BACE1 at 10 pM. Docking study showed that 2-aminobenzimidazole could form multiple hydrogen bonds and occupy S1/$2＇ pockets well.

摘要：Previous studies have shown that Ras/Raf/MEK/ERK signaling pathway is up-regulated in almost all cancer *** of this pathway by MEK inhibition is an efficient therapeutic approach of *** the present study,we described the discovery of 5-benzyl-2-phenylpyrimidin-4（3 H）-one as a novel skeleton of allosteric MEK *** acquired target compounds exhibited modest potency to inhibit MEK1 in Raf-MEK cascading assay,and docking studies revealed that the binding mode of the most potent compound（SJ3） was very similar to that of the well known diarylamine-based inhibitor（PD0325901）.The results provided valuable guidance for further optimizations on this novel scaffold to achieve druggable molecules.

摘要：pharmaceutical comprehensive study(PCS) is a new system of experimental teaching in China, which integrates multidisciplinary pharmaceutical knowledge and covers the basic process of new drug discovery. To explore the feasibility of this experiment teaching system and mode, we developed PCS as an elective course. The PCS is designed with two sections: pharmaceutical comprehensive design(PCD) and pharmaceutical comprehensive experiment(PCE). The PCD section includes literature review, comprehensive project design and oral examination. PCE can be divided into four parts: synthesis, quantitative determination, pharmacodynamic evaluation, and formulation and quality determination. Course grade was determined by experimental performance, written report, literature review, new project design and oral examination. The learning interest, experimental ability, theoretical level and literature retrieval ability, team spirit and interpersonal skills have been all significantly improved among students taking this course. A survey was administered at the end of the semester to the enrolled students. The responses were reported as percentages, and the feedback was positive. The course was highly recommended by the teaching inspection committee. This new course plays an important role in developing students’ creativity and comprehensive ability. It could help students understand the focus and features of every secondary discipline, as well as establish scientific and reasonable knowledge system. Most students can better understand the process of drug research after this course.

摘要：Based on the structure of compound B51（IC_（50） = 37.4 μM）, which was discovered as hit in a previous virtual screen, a series of methylisoxazole/isothiazole amide derivatives were designed and synthesized as BACE1 inhibitors. The methoxyphenylpyrimidone fragment of B51 was transformed into a methoxyphenylmethylisoxazole/isothiazole moiety to reduce the molecular weight while retaining the ability to fit into the S1＇ and S2＇ subpocket of BACE1 as predicted by docking studies. The effects of BACE1 inhibition and the structure-activity relationships were analyzed. Among all 20 designed compounds, 5t exhibited almost 10-fold improved potency（IC_（50） = 5.33 μM） compared to B51 in the BACE1 inhibition assay. Additionally, it has exhibited ＂rapid binding, slow dissociation＂ kinetics in SPR analysis, suggesting a longer inhibitory effect than B51. All acquired methylisoxazole/isothiazole derivatives were small in size and safe to normal cells, which allow them represent a novel scaffold for BACE1 inhibitor design.

摘要：Three series of novel anti-immunodeficiency virus 1 （HIV-1） dual （RT/1N） inhibitors were rationally designed by introducing a functioning diketo acid （DKA） into pyridin-2-one scaffold. To efficiently analyze inhibitory activity, these compounds were screened against HIV-1 RT and IN respectively via surface plasmon resonance （SPR）, and active compounds were subsequently evaluated by enzyme assay. It was noteworthy that compound A2 exhibited moderate activity against both HIV-1 RT and IN. This result provided information for further development of pyridinone analogues as potent dual HIV-1 inhibitors.