BACKGROUND & AIMS: :A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS(B)-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar=4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLS(B)-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9.

背景与目标： ：合成了一系列9-O-（3-芳基-2-炔丙基）肟酮醇酯8，并评价了其体外抗菌活性。与克拉霉素和阿奇霉素相比，在8、8b-8d和8h-8l中显示出对诱导性MLS（B）耐药和外流耐药病原体的效力显着提高。特别是8i（Ar = 4-异喹啉基）对组成型MLS（B）耐药的肺炎链球菌的MIC为0.064μg/ mL，对耐甲氧西林的金黄色葡萄球菌和耐甲氧西林的金黄色葡萄球菌的MIC为0.032-0.064μg/ mL 。具有丙基接头的类似物10比相应的含有丙炔基和丙烯基接头的8和9的效力差。进行了对接研究，以了解8和9系列的结合模式并合理化8和9 SAR中的差异。

BACKGROUND & AIMS: :Intrinsic flexibility of DNA has hampered the development of efficient protein-DNA docking methods. In this study we extend HADDOCK (High Ambiguity Driven DOCKing) [C. Dominguez, R. Boelens and A. M. J. J. Bonvin (2003) J. Am. Chem. Soc. 125, 1731-1737] to explicitly deal with DNA flexibility. HADDOCK uses non-structural experimental data to drive the docking during a rigid-body energy minimization, and semi-flexible and water refinement stages. The latter allow for flexibility of all DNA nucleotides and the residues of the protein at the predicted interface. We evaluated our approach on the monomeric repressor-DNA complexes formed by bacteriophage 434 Cro, the Escherichia coli Lac headpiece and bacteriophage P22 Arc. Starting from unbound proteins and canonical B-DNA we correctly predict the correct spatial disposition of the complexes and the specific conformation of the DNA in the published complexes. This information is subsequently used to generate a library of pre-bent and twisted DNA structures that served as input for a second docking round. The resulting top ranking solutions exhibit high similarity to the published complexes in terms of root mean square deviations, intermolecular contacts and DNA conformation. Our two-stage docking method is thus able to successfully predict protein-DNA complexes from unbound constituents using non-structural experimental data to drive the docking.

背景与目标： ：DNA的固有灵活性已阻碍了有效的蛋白质-DNA对接方法的发展。在这项研究中，我们扩展了HADDOCK（高歧义性驱动DOCKing）[C。 Dominguez，R.Boelens和A.M.J.J.Bonvin（2003）J.Am.化学Soc。 125，1731-1737]明确涉及DNA的灵活性。 HADDOCK使用非结构性实验数据来驱动刚体能量最小化，半柔性和水提纯阶段的对接。后者允许所有DNA核苷酸和蛋白质残基在预测界面处具有柔韧性。我们评估了由噬菌体434 Cro，大肠杆菌Lac头饰和噬菌体P22 Arc形成的单体阻遏物-DNA复合物的方法。从未结合的蛋白质和典型的B-DNA开始，我们正确地预测了复合物的正确空间分布以及已发布复合物中DNA的特定构象。该信息随后用于生成预先弯曲和扭曲的DNA结构的库，该库用作第二轮对接的输入。最终的顶级解决方案在均方根偏差，分子间接触和DNA构象方面与已发表的复合物具有高度相似性。因此，我们的两阶段对接方法能够使用非结构性实验数据来驱动对接，从而从未结合的成分中成功预测蛋白质-DNA复合物。

BACKGROUND & AIMS: :Specific docking interactions between mitogen-activated protein kinases (MAPKs), their regulators, and their downstream substrates, are crucial for efficient and accurate signal transmission. To identify novel substrates of the c-Jun N-terminal kinase (JNK) family of MAPKs, we searched the human genome for proteins that contained (1), a predicted JNK-docking site (D-site); and (2), a cluster of putative JNK target phosphosites located close to the D-site. Here we describe a novel JNK substrate that emerged from this analysis, the functionally uncharacterized protein smoothelin-like 2 (SMTNL2). SMTNL2 protein bound with high-affinity to multiple MAPKs including JNK1-3 and ERK2; furthermore, the identity of conserved amino acids in the predicted docking site (residues 180-193) was necessary for this high-affinity binding. In addition, purified full-length SMTNL2 protein was phosphorylated by JNK1-3 in vitro, and this required the integrity of the D-site. Using mass spectrometry and mutagenesis, we identified four D-site-dependent phosphoacceptor sites in close proximity to the docking site, at S217, S241, T236 and T239. A short peptide comprised of the SMTNL2 D-site inhibited JNK-mediated phosphorylation of the ATF2 transcription factor, showing that SMTNL2 can compete with other substrates for JNK binding. Moreover, when transfected into HEK293 cells, SMTNL2 was phosphorylated by endogenous JNK in a D-site dependent manner, on the same residues identified in vitro. SMTNL2 protein was expressed in many mammalian tissues, with a notably high expression in skeletal muscle. Consistent with the hypothesis that SMTNL2 has a function in skeletal muscle, SMTNL2 protein expression was strongly induced during the transition from myoblasts to myotubes in differentiating C2C12 cells.

背景与目标： ：有丝分裂原激活的蛋白激酶（MAPK），其调节剂及其下游底物之间的特定对接相互作用，对于有效而准确的信号传输至关重要。为了鉴定MAPKs的c-Jun N末端激酶（JNK）家族的新底物，我们在人类基因组中搜索了包含（1），一个预测的JNK停靠位点（D-site）的蛋白质； （2），位于D位点附近的一组推测的JNK目标磷酸位点。在这里，我们描述了一种从这种分析中出现的新型JNK底物，即功能上未表征的蛋白质平滑蛋白样2（SMTNL2）。 SMTNL2蛋白与包括JNK1-3和ERK2在内的多个MAPK高亲和力结合；此外，对于这种高亲和力结合而言，在预测的对接位点（残基180-193）中保守氨基酸的身份是必需的。此外，纯化的全长SMTNL2蛋白在体外被JNK1-3磷酸化，这需要D位点的完整性。使用质谱和诱变，我们在靠近对接位点的S217，S241，T236和T239处确定了四个D-位点依赖性磷酸受体位点。由SMTNL2 D位点组成的短肽抑制了JNK介导的ATF2转录因子的磷酸化，表明SMTNL2可以与其他底物竞争JNK结合。此外，当转染到HEK293细胞中时，SMTNL2被内源性JNK以D位点依赖性方式在体外鉴定的相同残基上磷酸化。 SMTNL2蛋白在许多哺乳动物组织中都有表达，在骨骼肌中有很高的表达。与SMTNL2在骨骼肌中具有功能的假设相一致，在分化C2C12细胞中从成肌细胞向肌管过渡期间，强烈诱导了SMTNL2蛋白表达。

BACKGROUND & AIMS: :Inhibition of urease results in Helicobacter pylori growth arrest in the stomach, promoting urease as promising targets for gastrointestinal ulcer therapy. Twenty hybrid derivatives of flavonoid scaffold and hydroxamic acid, β-hydroxy-β-phenylpropionylhydroxamic acids, were therefore synthesized and evaluated against H. pylori urease. Biological evaluation of these compounds showed improved urease inhibition exhibiting micromolar to mid-nanomolar IC50 values. Most importantly, 3-(3-chlorophenyl)-3-hydroxypropionyl-hydroxamic acid (6g) exhibited high potency with IC50 of 0.083±0.004 μM and Ki of 0.014±0.003 μM, indicating that 6g is an excellent candidate to develop novel antiulcer agent. A mixture of competitive and uncompetitive mechanism was putatively proposed to understand the inconsistency between the crystallographic and kinetic studies for the first time, which is supported by our molecular docking studies.

背景与目标： ：脲酶的抑制导致幽门螺杆菌在胃中的生长停滞，促进脲酶成为胃肠道溃疡治疗的有希望的靶标。因此，合成了黄酮类支架和异羟肟酸的二十种杂合衍生物，β-羟基-β-苯基丙酰基异羟肟酸，并针对幽门螺杆菌脲酶进行了评估。这些化合物的生物学评估表明，尿素酶抑制作用得到改善，表现出微摩尔至中纳摩尔级的IC50值。最重要的是，3-（3-氯苯基）-3-羟基丙酰基-异羟肟酸（6g）表现出很高的效力，IC50为0.083±0.004μM，Ki为0.014±0.003μM，表明6g是开发新型抗溃疡药的极佳候选药物。为了首次了解晶体学和动力学研究之间的矛盾，提出了一种竞争机制和非竞争机制的混合物，这是我们的分子对接研究所支持的。

BACKGROUND & AIMS: :This research firstly investigated the inhibitory effect of isoquercitrin (ISQ) on Ovalbumin (OVA) glycation. The mechanism was elucidated through the interaction between OVA and ISQ, and changes in glycation sites and degree of each site as deduced by spectroscopy, spectrometry and molecular docking. ISQ significantly inhibited OVA glycation by attenuating the conformational change induced by glycation. It quenched the fluorescence of Trp via static mechanism, and exposed Trp residues to a more hydrophobic surroundings. Formation of OVA-ISQ complex was a endothermic processing driven by hydrophobic interactions, van der Waals forces and hydrogen bonds. LC-Orbitrap-MS/MS revealed that ISQ altered the location of glycation and alleviated the glycation degree of most sites. Molecular docking results indicated that ISQ inserted into the hydrophobic pocket of OVA with six hydrogen bonds and one π-π stacking formed between ISQ and the amino acid residues of OVA, leading to the altered glycation activity of some sites.

背景与目标： ：本研究首先研究了异槲皮苷（ISQ）对卵清蛋白（OVA）糖基化的抑制作用。通过OVA和ISQ之间的相互作用以及通过光谱学，光谱学和分子对接推导的糖基化位点和每个位点的程度的变化阐明了该机理。 ISQ通过减弱糖基化诱导的构象变化来显着抑制OVA糖基化。它通过静态机制淬灭了Trp的荧光，并使Trp残基暴露于疏水性更高的环境中。 OVA-ISQ配合物的形成是由疏水相互作用，范德华力和氢键驱动的吸热过程。 LC-Orbitrap-MS / MS表明，ISQ改变了糖基化的位置并减轻了大多数位点的糖基化程度。分子对接结果表明，ISQ通过六个氢键插入到OVA的疏水口袋中，在ISQ与OVA的氨基酸残基之间形成一个π-π堆积，从而导致某些位点的糖基化活性发生了改变。

BACKGROUND & AIMS: :A novel series of 1-benzylquinazoline-2,4(1H,3H)-dione derivatives, 6a,b to 11a-e, was designed, synthesized, and evaluated for their anticancer activity against HepG2, HCT-116, and MCF-7 cells. Compounds 11b, 11e, and 11c were found to be the most potent derivatives of all tested compounds against the HepG2, HCT-116, and MCF-7 cancer cell lines, with GI50  = 9.16 ± 0.8, 5.69 ± 0.4, 5.27 ± 0.2 µM, 9.32 ± 0.9, 6.37 ± 0.7, 5.67 ± 0.5 µM, and 9.39 ± 0.5, 6.87 ± 0.7, 5.80 ± 0.4 µM, respectively. These compounds exhibited nearly the same activity as sorafenib against HepG2 and HCT-116 cells and a higher activity against MCF-7 cells (GI50  = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively). Also, these compounds displayed a lower activity than doxorubicin against HepG2 cells and a higher activity against HCT-116 and MCF-7 cells (GI50  = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively). The most active antiproliferative derivatives, 6a,b, 8, 9, and 11a-e, were selected to evaluate their enzymatic inhibitory activity against VEGFR-2. Compounds 11b, 11e, and 11c potently inhibited VEGFR-2 at IC50 values of 0.12 ± 0.02, 0.12 ± 0.02, and 0.13 ± 0.02 µM, respectively, which are nearly equipotent as sorafenib IC50 value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.

背景与目标： ：设计，合成了一系列新型的1-苄基喹唑啉-2,4（1H，3H）-二酮衍生物6a，b至11a-e，并评估了其对HepG2，HCT-116和MCF-的抗癌活性7个单元格。已发现化合物11b，11e和11c是所有测试化合物针对HepG2，HCT-116和MCF-7癌细胞系最有效的衍生物，GI50 = 9.16±0.8、5.69±0.4、5.27±0.2μM ，9.32±0.9、6.37±0.7、5.67±0.5μM和9.39±0.5、6.87±0.7、5.80±0.4μM。这些化合物显示出与索拉非尼相同的针对HepG2和HCT-116细胞的活性，并且具有较高的针对MCF-7细胞的活性（分别为GI50 = 9.18±0.6、5.47±0.3和7.26±0.3 M）。而且，这些化合物显示出比阿霉素更低的​​针对HepG2细胞的活性和更高的针对HCT-116和MCF-7细胞的活性（GI50分别为7.94±0.6、8.07±0.8和6.75±0.4μM）。选择活性最高的抗增殖衍生物6a，b，8、9和11a-e，以评估其对VEGFR-2的酶抑制活性。化合物11b，11e和11c分别以0.12±±0.02、0.12±±0.02和0.13±0.02μm的IC50值有效抑制VEGFR-2，这与索拉非尼的IC50值（0.10±±0.02μm）几乎相等。此外，对所有合成的化合物进行了分子对接研究，以评估它们的结合模式和对VEGFR-2活性位点的亲和力。

BACKGROUND & AIMS: :Rab3a is a small GTP binding protein associated with presynaptic vesicles that is thought to regulate vesicle targeting to active zones. Although this rab3a function implies that vesicle docking and action potential-evoked release might be inhibited in rab3a gene-deleted synapses, such inhibition has never been demonstrated. To investigate vesicle docking at the neuromuscular junction of rab3a gene-deleted (rab3a(-)) mice, we performed electron microscopy analysis of the diaphragm slow-fatigue (type I) synapses. We found a significant (26%) reduction in the number of vesicles docked to the presynaptic membrane in rab3a(-) terminals, although intraterminal vesicles were not affected. Aiming to detect possible changes in quantal release due to rab3a gene deletion, we minimized the variability between preparations employing focal recordings of synaptic responses from visualized type I endplates. We found a significant decrease in both evoked (27% reduction in quantal content) and spontaneous (28% reduction in mini frequency) quantal release. The decrease in the evoked release produced by rab3a deletion was most pronounced at reduced extracellular Ca(2+) concentrations (over 50% decrease at 0.5 and 0.2 mM Ca(2+)). By manipulating extracellular calcium, we demonstrated that calcium cooperativity is not altered in rab3a(-) synapses, however calcium sensitivity of quantal release is affected. Thus, we demonstrated that rab3a positively regulates docking and basal quantal release at the mouse neuromuscular junction. This result is consistent with the proposed role of rab3a in trafficking and targeting vesicles to the active zones.

背景与目标： ：Rab3a是与突触前囊泡相关的一种小GTP结合蛋白，被认为可调节将囊泡靶向活性区域。尽管此rab3a功能暗示在rab3a基因缺失的突触中囊泡对接和动作电位诱发的释放可能受到抑制，但这种抑制作用从未得到证实。若要研究囊泡停泊在rab3a基因缺失的（rab3a（-））小鼠的神经肌肉接头处，我们进行了隔膜慢疲劳（I型）突触的电子显微镜分析。我们发现停泊在rab3a（-）终端突触前膜的囊泡数量显着减少（26％），尽管终端内囊泡不受影响。为了检测由于rab3a基因缺失而导致的定量释放的可能变化，我们使用可视化I型终板突触反应的聚焦记录，将制剂之间的变异性最小化。我们发现诱发的（数量含量减少27％）和自发的（最小频率减少28％）定量释放均显着降低。 rab3a删除产生的诱发释放的减少在降低的细胞外Ca（2）浓度下最为明显（在0.5和0.2 mM Ca（2）处降低了50％以上）。通过操纵细胞外钙，我们证明了rab3a（-）突触中钙的协同作用并没有改变，但是钙对定量释放的敏感性受到影响。因此，我们证明了rab3a积极调节小鼠神经肌肉连接处的对接和基础定量释放。此结果与rab3a在贩运和将囊泡靶向活性区域中的拟议作用一致。

BACKGROUND & AIMS: :A new optimization model of molecular docking is proposed, and a fast flexible docking method based on an improved adaptive genetic algorithm is developed in this paper. The algorithm takes some advanced techniques, such as multi-population genetic strategy, entropy-based searching technique with self-adaptation and the quasi-exact penalty. A new iteration scheme in conjunction with above techniques is employed to speed up the optimization process and to ensure very rapid and steady convergence. The docking accuracy and efficiency of the method are evaluated by docking results from GOLD test data set, which contains 134 protein-ligand complexes. In over 66.2% of the complexes, the docked pose was within 2.0 A root-mean-square deviation (RMSD) of the X-ray structure. Docking time is approximately in proportion to the number of the rotatable bonds of ligands.

背景与目标： ：提出了一种新的分子对接优化模型，并提出了一种基于改进的自适应遗传算法的快速柔性对接方法。该算法采用了多种群遗传策略，具有自适应性的基于熵的搜索技术和准精确罚分等先进技术。结合以上技术采用了新的迭代方案，以加快优化过程并确保非常快速和稳定的收敛。通过GOLD测试数据集的对接结果评估该方法的对接精度和效率，该数据集包含134个蛋白质-配体复合物。在超过66.2％的配合物中，对接位姿在X射线结构的2.0 A均方根偏差（RMSD）范围内。对接时间大约与配体可旋转键的数量成比例。

BACKGROUND & AIMS: :The series of symmetrical and unsymmetrical isoquinolinium-5-carbaldoximes was designed and prepared for cholinesterase reactivation purposes. The novel compounds were evaluated for intrinsic acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) inhibition, when the majority of novel compounds resulted with high inhibition of both enzymes and only weak inhibitors were selected for reactivation experiments on human AChE or BChE inhibited by sarin, VX, or paraoxon. The AChE reactivation for all used organophosphates was found negligible if compared to the reactivation ability of obidoxime. Importantly, two compounds were found to reactivate BChE inhibited by sarin or VX better to obidoxime at human attainable concentration. One compound resulted as better reactivator of NEMP (VX surrogate)-inhibited BChE than obidoxime. The in vitro results were further rationalized by molecular docking studies showing future directions on designing potent BChE reactivators.

背景与目标： ：设计并制备了一系列对称和不对称的异喹啉鎓-5-carbaldoximes，用于胆碱酯酶的活化。当大多数新型化合物对两种酶均具有高度抑制作用且仅选择弱抑制剂用于沙林，VX抑制的人AChE或BChE的再活化实验时，评估了这些新型化合物的内在乙酰胆碱酯酶（AChE）或丁酰胆碱酯酶（BChE）抑制作用。或对氧磷。如果与Obobxime的再活化能力相比，发现所有用过的有机磷酸酯的AChE再活化可以忽略不计。重要的是，发现两种化合物能够在人可达到的浓度下将沙林或VX抑制的BChE更好地活化为obidoxime。一种化合物产生了比奥比多肟更好的NEMP（VX替代物）抑制的BChE活化剂。通过分子对接研究进一步合理化了体外结果，显示了设计有效BChE活化剂的未来方向。

BACKGROUND & AIMS: :Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) play a key role in membrane fusion in the secretory pathway. In vitro, SNAREs spontaneously assemble into helical SNARE complexes with the transmembrane domains at the C-terminal end. During fusion, SNAREs are thought to bridge the two membranes and assemble in a zipper-like fashion, pulling the membranes together and initiating fusion. However, it is not clear to what extent SNARE assembly contributes to membrane attachment and membrane fusion. Using the neuronal SNAREs synaptobrevin (VAMP), SNAP-25, and syntaxin as examples, we show here that liposomes containing synaptobrevin firmly attach to planar surfaces containing immobilized syntaxin. Attachment requires the formation of SNARE complexes because it is dependent on the presence of SNAP-25. Binding is competed for by soluble SNARE fragments, with noncognate SNAREs such as endobrevin (VAMP8), VAMP4, and VAMP7 (Ti-VAMP) being effective but less potent in some cases. Furthermore, although SNAP-23 is unable to substitute for SNAP-25 in the attachment assay, it forms complexes of comparable stability and is capable of substituting in liposome fusion assays. Vesicle attachment is initiated by SNARE assembly at the N-terminal end of the helix bundle. We conclude that SNAREs can indeed form stable trans-complexes that result in vesicle attachment if progression to fusion is prevented, further supporting the zipper model of SNARE function.

背景与目标： ：可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）在分泌途径的膜融合中起关键作用。在体外，SNARE自发组装成螺旋状的SNARE复合物，在C末端带有跨膜结构域。在融合过程中，SNARE被认为桥接了两个膜并以拉链状的方式组装，将膜拉在一起并开始融合。但是，尚不清楚SNARE组装在多大程度上有助于膜的附着和融合。以神经元SNAREs突触短纤维蛋白（VAMP），SNAP-25和语法素为例，我们在这里显示出含有突触短纤维蛋白的脂质体牢固地附着在含有固定化语法素的平面上。附着需要形成SNARE复合物，因为它取决于SNAP-25的存在。可溶性的SNARE片段竞争结合，其中非同源的SNARE（例如内皮素（VAMP8），VAMP4和VAMP7（Ti-VAMP））有效，但在某些情况下效力较弱。此外，尽管SNAP-23在附着测定中无法替代SNAP-25，但它形成了具有相当稳定性的复合物，并能够替代脂质体融合测定。囊泡的附着是由螺旋束N端的SNARE组装引发的。我们得出的结论是，如果防止融合进展，SNARE确实可以形成稳定的反式复合物，从而导致囊泡附着，从而进一步支持SNARE功能的拉链模型。

BACKGROUND & AIMS: :We present the fifth evaluation of docking and related scoring methods used in the community-wide experiment on the Critical Assessment of Predicted Interactions (CAPRI). The evaluation examined predictions submitted for a total of 15 targets in eight CAPRI rounds held during the years 2010-2012. The targets represented one the most diverse set tackled by the CAPRI community so far. They included only 10 "classical" docking and scoring problems. In one of the classical targets, the new challenge was to predict the position of water molecules in the protein-protein interface. The remaining five targets represented other new challenges that involved estimating the relative binding affinity and the effect of point mutations on the stability of designed and natural protein-protein complexes. Although the 10 classical CAPRI targets included two difficult multicomponent systems, and a protein-oligosaccharide complex with which CAPRI participants had little experience, this evaluation indicates that the performance of docking and scoring methods has remained quite robust. More remarkably, we find that automatic docking servers exhibit a significantly improved performance, with some servers now performing on par with predictions done by humans. The performance of CAPRI participants in the new challenges, briefly reviewed here, was mediocre overall, but some groups did relatively well and their approaches suggested ways of improving methods for designing binders and for estimating the free energies of protein assemblies, which should impact the field of protein modeling and design as a whole.

背景与目标： ：我们提出了对社区进行的对预测互动的关键评估（CAPRI）的对接和相关评分方法的第五次评估。评估审查了在2010-2012年间举行的八轮CAPRI回合中针对15个目标提交的预测。这些目标是迄今为止CAPRI社区解决的最多样化的目标之一。他们仅包含10个“经典”对接和得分问题。在经典目标之一中，新的挑战是预测水分子在蛋白质-蛋白质界面中的位置。其余五个目标代表了其他新挑战，涉及估计相对结合亲和力和点突变对设计的天然蛋白质-蛋白质复合物稳定性的影响。尽管10个经典的CAPRI目标包括两个困难的多组分系统，以及一个CAPRI参与者缺乏经验的蛋白质-寡糖复合物，但是该评估表明对接和评分方法的性能仍然相当可靠。更值得注意的是，我们发现自动对接服务器的性能大大提高，有些服务器现在的性能与人类的预测相当。在这里简要回顾的CAPRI参与者在新挑战中的表现总体上中等，但是一些小组的表现相对较好，他们的方法提出了改进设计粘合剂的方法和估计蛋白质组装体自由能的方法，这将影响该领域整个蛋白质建模和设计。

BACKGROUND & AIMS: BACKGROUND:Ensemble docking has proven useful in drug discovery and development. It increases the hit rate by incorporating receptor flexibility into molecular docking as demonstrated on important drug targets including G-protein-coupled receptors (GPCRs). Adenosine A1 receptor (A1AR) is a key GPCR that has been targeted for treating cardiac ischemia-reperfusion injuries, neuropathic pain and renal diseases. Development of allosteric modulators, compounds binding to distinct and less conserved GPCR target sites compared with agonists and antagonists, has attracted increasing interest for designing selective drugs of the A1AR. Despite significant advances, more effective approaches are needed to discover potent and selective allosteric modulators of the A1AR. METHODS:Ensemble docking that integrates Gaussian accelerated molecular dynamic (GaMD) simulations and molecular docking using Autodock has been implemented for retrospective docking of known positive allosteric modulators (PAMs) in the A1AR. RESULTS:Ensemble docking outperforms docking of the receptor cryo-EM structure. The calculated docking enrichment factors (EFs) and the area under the receiver operating characteristic curves (AUC) are significantly increased. CONCLUSIONS:Receptor ensembles generated from GaMD simulations are able to increase the success rate of discovering PAMs of A1AR. It is important to account for receptor flexibility through GaMD simulations and flexible docking. GENERAL SIGNIFICANCE:Ensemble docking is a promising approach for drug discovery targeting flexible receptors.

背景与目标： 背景：集成对接已被证明在药物发现和开发中很有用。如重要药物靶标（包括G蛋白偶联受体（GPCR））所示，它通过将受体的柔韧性结合到分子对接中来提高命中率。腺苷A1受体（A1AR）是关键的GPCR，已被靶向治疗心脏缺血-再灌注损伤，神经性疼痛和肾脏疾病。与激动剂和拮抗剂相比，变构调节剂（与不同且不那么保守的GPCR靶位点结合的化合物）的开发吸引了越来越多的兴趣来设计A1AR选择性药物。尽管取得了重大进展，但仍需要更有效的方法来发现A1AR的有效和选择性变构调节剂。
方法：集成了高斯加速分子动力学（GaMD）模拟和使用Autodock进行分子对接的集成对接已实现了对A1AR中已知的正构构调节剂（PAM）的追溯对接。
结果：整体对接优于对接体cryo-EM结构的对接。计算出的对接富集因子（EFs）和接收器工作特性曲线（AUC）下的面积显着增加。
结论：GaMD模拟产生的受体集合能够提高发现A1AR PAM的成功率。重要的是要通过GaMD模拟和灵活的对接考虑受体的灵活性。
一般意义：整合对接是一种针对靶向柔性受体的药物发现的有前途的方法。

BACKGROUND & AIMS: :The biological and clinical heterogeneity of neuroblastoma is closely associated with signaling pathways that control cellular characteristics such as proliferation, survival and differentiation. The Shc family of docking proteins is important in these pathways by mediating cellular signaling. In this study, we analysed the expression levels of ShcA and ShcC proteins in 46 neuroblastoma samples and showed that a significantly higher level of ShcC protein is observed in neuroblastomas with poor prognostic factors such as advanced stage and MYCN amplification (P<0.005), whereas the expression level of ShcA showed no significant association with these factors. Using TNB1 cells that express a high level of ShcC protein, it was demonstrated that knockdown of ShcC by RNAi caused elevation in the phosphorylation of ShcA, which resulted in sustained extracellular signal-regulated kinase activation and neurite outgrowth. The neurites induced by ShcC knockdown expressed several markers of neuronal differentiation suggesting that the expression of ShcC potentially has a function in inhibiting the differentiation of neuroblastoma cells. In addition, marked suppression of in vivo tumorigenicity of TNB1 cells in nude mice was observed by stable knockdown of ShcC protein. These findings indicate that ShcC is a therapeutic target that might induce differentiation in the aggressive type of neuroblastomas.

背景与目标： ：神经母细胞瘤的生物学和临床异质性与控制细胞特征（例如增殖，存活和分化）的信号通路密切相关。 Shc家族的对接蛋白通过介导细胞信号传导在这些途径中很重要。在这项研究中，我们分析了46个神经母细胞瘤样品中ShcA和ShcC蛋白的表达水平，并发现在预后较差的神经母细胞瘤（如晚期和MYCN扩增）中观察到ShcC蛋白水平显着升高（P <0.005），而ShcA的表达水平与这些因素无显着相关性。使用表达高水平ShcC蛋白的TNB1细胞，已证明RNAi抑制ShcC会导致ShcA磷酸化水平升高，从而导致持续的细胞外信号调节激酶激活和神经突生长。 ShcC敲低诱导的神经突表达了几种神经元分化标记，这表明ShcC的表达可能具有抑制神经母细胞瘤细胞分化的功能。另外，通过稳定敲除ShcC蛋白观察到裸鼠体内TNB1细胞体内致瘤性的显着抑制。这些发现表明，ShcC是一种治疗靶标，可能在侵袭性类型的神经母细胞瘤中诱导分化。

BACKGROUND & AIMS: :Analysis of trajectories from our rigid-body dynamics simulation package, BioSimz, is used to find regions on the surface of unbound proteins that form frequent and tenacious encounter complexes with their binding partner. Binding partners are significantly more likely to sojourn around true binding regions than around the remainder of the protein surface. This information is used to restrict the search space for flexible protein-protein docking using our SwarmDock algorithm, reducing the computational expense of docking, and improving or matching the ranking of successfully docked poses for all but four of 26 test cases. Running the simulations with external crowder proteins, at near physiological concentration, further enhances the binding region, compared to simulations without external crowders. Information gleaned from these simulations can give mechanistic insights into binding events. The application of these techniques to CAPRI targets 32 and 38-40 is discussed.

背景与目标： ：通过我们的刚体动力学仿真程序包BioSimz对轨迹进行分析，可用于发现未结合蛋白表面上与结合伴侣形成频繁且顽强的复合体的区域。结合伴侣比真正的结合区域更可能停留在真正的结合区域附近。该信息用于限制使用我们的SwarmDock算法进行灵活的蛋白质-蛋白质对接的搜索空间，从而减少对接的计算量，并改善或匹配26个测试用例中除四个以外的所有成功对接姿势的排名。与没有外部拥挤物的模拟相比，使用外部拥挤物蛋白质在接近生理浓度的条件下运行模拟可进一步增强结合区域。从这些模拟中收集的信息可以为绑定事件提供机械的见解。讨论了这些技术对CAPRI目标32和38-40的应用。

BACKGROUND & AIMS: :The article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of 3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl analogs reported for DPP-IV inhibition using PHASE module of Schrodinger software. The present works also encompass molecular interaction study of 3-amino-4-(2- cyanopyrrolidide)pyrrolidinyl analogs on maestro 8.5 workstation. The Phase study module comprises the five points pharmacophore model (AAHPR.617), consisting two hydrogen bond acceptor (A), one Hydrophobic (H), one Positive(P) and one aromatic ring (R) and with discrete geometries as pharmacophoric feature. The developed pharmacophore model was used to derive a predictive atom-based 3D QSAR model. The obtained 3D QSAR model has an excellent correlation coefficient value (r2=0.9926) along with good statistical significance as shown by high Fisher ratio (F=671.7). The model also exhibits good predictive power, which is confirmed by high value of cross validated correlation coefficient (q2 = 0.7311). The QSAR model suggests that hydrophobic and aromatic characters are crucial for the DPP-IV inhibitory activity. The QSAR model also suggests that the inclusion of hydrophobic substituents would enhance the DPP-IV inhibition. In addition to the hydrogen bond acceptor, hydrophobic character, electro withdrawing character positively contributes to the DPP-IV inhibition. This study provides a set of guidelines for designing compounds with better DPP-IV inhibitory potency.

背景与目标： ：本文介绍了使用Schrodinger软件的PHASE模块开发的稳健药效团模型的开发以及报道的可抑制DPP-IV的3-氨基-4-（2-氰基吡咯烷酮）吡咯烷基类似物的结构活性关系分析。本工作还包括在大师8.5工作站上的3-氨基-4-（2-氰基吡咯烷）吡咯烷基类似物的分子相互作用研究。阶段研究模块包括五点药效团模型（AAHPR.617），由两个氢键受体（A），一个疏水性（H），一个正性（P）和一个芳香环（R）组成，并且具有离散的几何结构作为药效团特征。开发的药效团模型用于推导基于原子的预测3D QSAR模型。所获得的3D QSAR模型具有出色的相关系数值（r2 = 0.9926），并且具有较高的统计显着性，如高费舍尔比率（F = 671.7）所示。该模型还显示出良好的预测能力，这可以通过交叉验证的相关系数的高值来确认（q2 = 0.7311）。 QSAR模型表明疏水和芳香特性对DPP-IV抑制活性至关重要。 QSAR模型还表明，包含疏水取代基将增强DPP-IV抑制作用。除氢键受体外，疏水性，电撤离性对DPP-IV抑制也有积极作用。这项研究为设计具有更好的DPP-IV抑制能力的化合物提供了一套指导方针。