DNA polymerase theta (Polθ or POLQ) is an attractive target for treating BRCA-deficient cancers. In the present work, several computational approaches were employed for the design and discovery of novel POLQ helicase domain inhibitors. A dataset was constructed by curating a total of 781 known inhibitors, which were used to develop binary classification models using random forests to distinguish between highly and weakly active inhibitors. The Matthews correlation coefficient of the consensus model reached 0.771 for the test set. A virtual screening procedure of 3.4 million molecules was conducted based on shape similarity and predictions from the consensus model to identify four hits and a favorable benzothiazole moiety. A molecular generation model was trained using molecules from both the curated dataset and the identified hits to generate potential inhibitors, which were subsequently predicted by the consensus model. Finally, eight compounds were selected and synthesized for biochemical testing, leading to the identification of compound 19, which had a novel scaffold and acceptable potency: inhibition rates of 80.7

Glycoprotein VI (GPVI) plays an important role in platelet aggregation, and inhibition of GPVI may block thrombosis with a low bleeding risk, thus making GPVI a promising antithrombotic target. In this paper, the binding mode of losartan, a known GPVI inhibitor, was investigated using molecular docking and molecular dynamics methods as well. Docking results can determine the location site of the phenyl tetrazole group of losartan, but the direction of the two substitute groups on imidazole ring is uncertain. Therefore, two sample conformations were selected, and long-time molecular dynamics simulations were carried out. The rotatable bond of C–N connecting the imidazole ring and the middle benzene ring was monitored during the simulation. The results showed that this dihedral angle is mostly distributed at about [Formula: see text] for both systems, implying that this conformation is the dominant conformation. The switchable conformation may be the reason for low activity of losartan to GPVI. Losartan1 system was well equilibrated and selected as the receptor to perform drug repurposing screening, and several drugs with a similar binding mode as losartan were identified. Our study may enhance the mechanism understanding of GPVI receptor, giving insights into the design and discovery of novel GPVI inhibitors.

A series of novel thienopyridine derivatives were designed and synthesized as P2Y(12) receptor inhibitors. Several solid compounds were assessed for inhibitory effect where they exhibited stronger potency than clopidogrel. Compound 6b and 6g were evaluated for metabolism to verify that they could overcome clopidogrel resistance and for toxicity where they showed lower toxicity than prasugrel. Compound 6b exhibited lower risk of bleeding than prasugrel and showed good stability under stress testing. Overall, as a promising antiplatelet agent, representative compound 6b showed the following advantages: (1) no drug resistance for CYP2C19 poor metabolizers; (2) higher potency than clopidogrel; (3) lower toxicity than prasugrel; (4) lower risk of bleeding than prasugrel; (5) good stability as a non-salt solid.

目的 活化Ⅸ因子(FⅨa)是针对静脉血栓疾病研究中十分具有吸引力的靶点.为了寻找安全、有效、用药便捷的新型口服抗凝药物,针对FⅨa靶点设计了18个吡咯烷类化合物.方法 经过烷基化反应、酰基化反应、迈克尔加成反应、缩合反应、水解反应等对目标化合物进行化学合成,所获得的化合物经过1H-NMR、MS等手段进行了结构确证;采用离体酶抑制法测定化合物的FⅨa抑制活性.结果 发现了苗头化合物Ai显示出FⅨa抑制活性.结论 通过分子对接模拟化合物Ai和阳性对照CFM-184与靶点的作用模式,揭示了二者的差异,为后续FⅨa抑制剂的研发提供思路.

Protease-activated receptor 4 (PAR4) is a promising target for antiplatelet therapy. In this study, homology modeling and molecular docking methods were used to investigate the binding modes of PAR4 agonists and antagonists. The outcomes show that agonists have good docking scores, and they also form more hydrogen bonds with PAR4 than antagonists. To reveal the different conformational changes caused by agonist and antagonist, molecular dynamic simulations were carried out on three selected PAR4 systems. Simulation results show that PAR4 activation involves breaking interactions of 3–7 lock switch (Try157 and Tyr322) and ionic lock switch (Arg188 and Asp173), and formation of transmission switch among Tyr161, Asn300 and Phe296. In addition, principal component analysis (PCA) indicates that the major change for agonist bound system takes place in the intracellular region while that for antagonist bound system is in the extracellular region. The binding free energy of BMS-986120 is much lower than AYPGKF, suggesting high affinity of antagonist. Moreover, the electronegative aspartic residues Asp230 and Asp235 at ECL2 are important for PAR4 binding to agonist. Clarifying the PAR4 structural characteristics may be helpful to understand the activation mechanism, giving insights into the molecular design and discovery of novel potential PAR4 antagonists in the future.

We developed intelligent, star-shaped amphiphilic beta-cyclodextrin (beta-CD) co-polymer nanocarriers to circumvent the poor drug loading and water-solubility of beta-CD. The secondary hydroxyl groups of beta-CD were methylated to improve solubility, and the primary hydroxyl groups were conjugated with mPEG-b-PCL-SH through disulfide linkage to amplify the hydrophobic cavity and enhance the stability of the nanocarrier. A series of amphiphilic beta-CD block copolymers (CCPPs) differing in molecular weights were synthesized that could self-assemble into core-shell nanospheres measuring 50-70 nm in water. The different CCPP carriers were screened for their drug loading, encapsulation and release efficiencies, and CCPP-2 showed the highest drug loading capacity of 31.9% by weight. These nanocarriers accumulated at the tumor site through the EPR effect and released the drug in a controlled manner in the reductive tumor microenvironment, with negligible premature leakage and side effects. Therefore, CCPP-2 shows significant potential as a smart and efficient nanovehicle for anticancer drug delivery.

以5-三苯甲基-5,6,7,7a-四氢噻吩[3,2-c]吡啶-2（4H）-酮为起始原料,依次经酯化、脱保护和亲核取代反应合成了17个新型的N-（2-氧代-2-苯基乙基）-4,5,6,7-四氢噻吩并[3,2-c]吡啶酯（1a～1q）;并以2-溴-1-环丙基-2-（2-氟苯基）乙酮合成了新的普拉格雷衍生物（6）,其结构均经~1H NMR和MS（ESI）表征。并通过"ADP对大鼠血小板聚集的影响"的药效学模型初步评价了其抗血小板聚集活性。结果表明:1f,1p,1q和6对血小板聚集有一定的抑制作用,其中6在低剂量(3 mg·kg -1 )下的活性优于阳性对照药氯吡格雷。

The thienopyridines class of drugs used as P2Y12 receptor antagonists plays a vital role in antiplatelet therapy. To further optimized this compound class, we designed and synthesized a series of amino acid prodrugs of 2-hydroxytetrahydrothienopyridine. All compounds were then evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats and then ED50 and bleeding time of the most potent compounds were compared with commercial drugs. The results showed compound 5c could be a potent and safe candidate for further research.

2-Acetoxy-5-trityl-4,5,6,7-tetrahydrothieno[3,2-c] pyridine(4) was obtained by acetyla-tion and deprotection from 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one.Then 4 was condensed with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethanone to prepare 2-[2-(acetyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl) ethanone(5).5 was sali-fied to finally give prasugrel hydrochloride, with an overall yield of 75.0%.The structure was con-firmed by 1H NMR and MS(ESI).