• 【合成,体外筛选和作为乙酰胆碱酯酶和丁酰胆碱酯酶活化剂的异喹啉鎓5-咔哒肟的分子对接。】 复制标题 收藏 收藏
    DOI:10.1080/14756366.2019.1710501 复制DOI
    作者列表:Malinak D,Dolezal R,Hepnarova V,Hozova M,Andrys R,Bzonek P,Racakova V,Korabecny J,Gorecki L,Mezeiova E,Psotka M,Jun D,Kuca K,Musilek K
    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。
  • 【脂质体与反式-SNARE复合物介导的平面对接。】 复制标题 收藏 收藏
    DOI:10.1529/biophysj.108.129510 复制DOI
    作者列表:Vites O,Florin EL,Jahn R
    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。
  • 【CAPRI中的对接,得分和亲和力预测。】 复制标题 收藏 收藏
    DOI:10.1002/prot.24428 复制DOI
    作者列表:Lensink MF,Wodak SJ
    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。
  • 【变构调节剂在腺苷G蛋白偶联受体中的回顾性整体对接。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbagen.2020.129615 复制DOI
    作者列表:Bhattarai A,Wang J,Miao Y
    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。
  • 【ShcC对接蛋白在神经母细胞瘤分化中的独特作用。】 复制标题 收藏 收藏
    DOI:10.1038/onc.2008.413 复制DOI
    作者列表:Miyake I,Ohira M,Nakagawara A,Sakai R
    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。
  • 【检测和优化蛋白质-蛋白质对接遇到的复合物:考虑到大分子拥挤。】 复制标题 收藏 收藏
    DOI:10.1002/prot.22770 复制DOI
    作者列表:Li X,Moal IH,Bates PA
    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。
  • 【作为DPP-IV抑制剂的各种酰胺基和苄基取代的3-氨基-4-(2-氰基吡咯烷基)吡咯烷基类似物的3D QSAR和对接研究。】 复制标题 收藏 收藏
    DOI:10.2174/0929866511320090013 复制DOI
    作者列表:Agrawal R,Jain P,Dikshit SN,Jain S
    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。
  • 【1,2-苯并噻嗪1,1-二氧化物碳酰肼的α-葡萄糖苷酶抑制作用和分子对接研究。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Saddique FA,Ahmad M,Ashfaq UA,Ahmad MN,Anjum MN,Mohsin NA,Aslam S
    BACKGROUND & AIMS: :Diabetes Mellitus is a chronic disease in which the infected cells do not have the ability to produce sufficient amount of insulin that resulted in the abnormality of carbohydrates metabolism and an increase in blood glucose level. Long time exposure to Diabetes Mellitus resulted in failure or dysfunction of different organs like kidneys, nerves, heart, eyes, etc. A common practice to cure diabetes is the use of α-glucosidase inhibitors which help in lowering the blood glucose level. We presented 1,2-benzothiazine 1,1-dioxide derivatives as novel and more potent α-glucosidase inhibitors via their in vitro and in silico screenings. Excellent enzyme inhibitions were observed for compounds 2, 8, 10 and 12 having IC50 values of 6.91, 14.0, 4.2, 5.9 and 29.2μ respectively which were found better than the reference acarbose (IC50=38.31μM). Molecular docking studies suggested high binding energies and good binding interactions of these compounds with the active site residues of the receptor protein. A good agreement was found between the results of both modes of evaluation. Moreover, the envisioned candidates have a good potential to treat diabetes.
    背景与目标: :Diabetes Mellitus是一种慢性疾病,其中被感染的细胞无法产生足够量的胰岛素,从而导致碳水化合物代谢异常和血糖水平升高。长时间暴露于糖尿病会导致诸如肾脏,神经,心脏,眼睛等不同器官的衰竭或功能障碍。治疗糖尿病的一种常见做法是使用α-葡萄糖苷酶抑制剂来帮助降低血糖水平。通过体外和计算机筛选,我们提出了1,2-苯并噻嗪1,1-二氧化物衍生物,它们是新型且更有效的α-葡萄糖苷酶抑制剂。化合物2、8、10和12的IC50值分别为6.91、14.0、4.2、5.9和29.2μ,表现出优异的酶抑制作用,发现其优于参考阿卡波糖(IC50 =38.31μM)。分子对接研究表明这些化合物与受体蛋白的活性位点残基具有很高的结合能和良好的结合相互作用。在两种评估模式的结果之间都找到了很好的共识。此外,预想的候选人具有治疗糖尿病的良好潜力。
  • 【评论文章“关于评估姿态预测和富集因子的分子对接方法”。】 复制标题 收藏 收藏
    DOI:10.1021/ci600460h 复制DOI
    作者列表:Perola E,Walters WP,Charifson P
    BACKGROUND & AIMS: :The recent article "On Evaluating Molecular-Docking Methods for Pose Prediction and Enrichment Factors" (Chen H. et al. J. Chem. Inf. Model. 2006, 46, 401-415) contains a series of comments on a similar study we published in Proteins in 2004 (Perola et al. Proteins 2004, 56, 235-249). We believe that some of these comments are misleading, and we feel that an adequate response is in order.
    背景与目标: :最近的文章“关于评估姿势预测和富集因子的分子对接方法”(Chen H.等人,J。Chem。Inf。Model。2006,46,401-415)包含对类似研究的一系列评论我们在2004年的《蛋白质》杂志上发表了文章(Perola等人,《蛋白质》 2004,56,235-249)。我们认为,其中一些评论具有误导性,我们认为应该作出适当回应。
  • 【争取海湾战争疾病的治疗:共识性对接方法。】 复制标题 收藏 收藏
    DOI:10.1093/milmed/usz299 复制DOI
    作者列表:Jaundoo R,Bohmann J,Gutierrez GE,Klimas N,Broderick G,Craddock TJA
    BACKGROUND & AIMS: INTRODUCTION:Gulf War Illness (GWI) currently has no known cure and affects soldiers deployed during the Persian Gulf War. It is thought to originate from exposure to neurotoxicants combined with battlefield stress, and previous research indicates that treatment first involves inhibition of interleukin-2 and tumor necrosis factor alpha, followed by the glucocorticoid receptor. However, the off-target effects of pharmaceuticals hinder development of a drug treatment therapy. MATERIALS AND METHODS:AutoDock 4.2, AutoDock Vina, and Schrodinger's Glide were used to perform consensus docking, a computational technique where pharmaceuticals are screened against targets using multiple scoring algorithms to obtain consistent binding affinities. FDA approved pharmaceuticals were docked against the above-mentioned immune and stress targets to determine a drug therapy for GWI. Additionally, the androgen and estrogen targets were screened to avoid pharmaceuticals with off-target interactions. RESULTS:While suramin bound to both immune targets with high affinity, top binders of the hormonal and glucocorticoid targets were non-specific towards their respective proteins, possibly due to high structure similarity between these proteins. CONCLUSIONS:Development of a drug treatment therapy for GWI is threatened by the tight interplay between the immune and hormonal systems, often leading to drug interactions. Increasing knowledge of these interactions can lead to break-through therapies.
    背景与目标: 简介:海湾战争疾病(GWI)目前尚无治愈方法,会影响在波斯湾战争期间部署的士兵。据认为,这是由于暴露于神经毒物并伴随战场压力而引起的,以前的研究表明,治疗首先涉及抑制白介素2和肿瘤坏死因子α,然后抑制糖皮质激素受体。然而,药物的脱靶效应阻碍了药物治疗疗法的发展。
    材料与方法:使用AutoDock 4.2,AutoDock Vina和Schrodinger's Glide进行共识对接,这是一种计算技术,其中使用多种评分算法针对目标筛选药物以获得一致的结合亲和力。 FDA批准的药物与上述免疫和应激目标对接,以确定GWI的药物疗法。另外,筛选雄激素和雌激素靶标,以避免药物与靶标之间发生相互作用。
    结果:虽然苏拉明以高亲和力结合到两个免疫靶标上,但激素和糖皮质激素靶标的主要结合剂对其各自的蛋白质没有特异性,这可能是由于这些蛋白质之间的高度结构相似性所致。
    结论:免疫和激素系统之间的紧密相互作用威胁着GWI药物治疗疗法的发展,常常导致药物相互作用。对这些相互作用的了解不断增加,可能会带来突破性的疗法。
  • 【针对新的CAPRI挑战优化pyDock:对接基于同源性的模型,域结构域组装和蛋白质-RNA结合。】 复制标题 收藏 收藏
    DOI:10.1002/prot.22773 复制DOI
    作者列表:Pons C,Solernou A,Perez-Cano L,Grosdidier S,Fernandez-Recio J
    BACKGROUND & AIMS: :We describe here our results in the last CAPRI edition. We have participated in all targets, both as predictors and as scorers, using our pyDock docking methodology. The new challenges (homology-based modeling of the interacting subunits, domain-domain assembling, and protein-RNA interactions) have pushed our computer tools to the limits and have encouraged us to devise new docking approaches. Overall, the results have been quite successful, in line with previous editions, especially considering the high difficulty of some of the targets. Our docking approaches succeeded in five targets as predictors or as scorers (T29, T34, T35, T41, and T42). Moreover, with the inclusion of available information on the residues expected to be involved in the interaction, our protocol would have also succeeded in two additional cases (T32 and T40). In the remaining targets (except T37), results were equally poor for most of the groups. We submitted the best model (in ligand RMSD) among scorers for the unbound-bound target T29, the second best model among scorers for the protein-RNA target T34, and the only correct model among predictors for the domain assembly target T35. In summary, our excellent results for the new proposed challenges in this CAPRI edition showed the limitations and applicability of our approaches and encouraged us to continue developing methodologies for automated biomolecular docking.
    背景与目标: :我们在上一版CAPRI中描述了我们的结果。使用pyDock对接方法,我们参与了所有目标的预测和得分。新的挑战(基于相互作用的亚基的同源性建模,域-域组装和蛋白质-RNA相互作用)将我们的计算机工具推向了极限,并鼓励我们设计新的对接方法。总体而言,与以前的版本一致,结果是相当成功的,尤其是考虑到某些目标的高难度。我们的对接方法成功地在五个目标中用作预测指标或得分指标(T29,T34,T35,T41和T42)。此外,由于包含了预期参与相互作用的残基的可用信息,因此我们的方案在另外两种情况(T32和T40)中也将获得成功。在其余目标中(T37除外),大多数组的结果同样差。我们提交了未绑定目标T29的评分器中最佳的模型(配体RMSD中),蛋白质RNA靶T34的评分器中第二好的模型,以及结构域组装目标T35的预测因子中唯一正确的模型。总而言之,我们在此CAPRI版本中针对新提出的挑战所获得的出色结果表明了我们方法的局限性和适用性,并鼓励我们继续开发自动化生物分子对接的方法。
  • 【基于受体的化合物数据库的计算筛选:主要的对接评分引擎。】 复制标题 收藏 收藏
    DOI:10.2174/138920306778559377 复制DOI
    作者列表:Sperandio O,Miteva MA,Delfaud F,Villoutreix BO
    BACKGROUND & AIMS: :The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance with many new and exciting techniques. The number of protein structures and/or chemical ligands is constantly growing, through the use of parallel chemistry, X-ray crystallography, NMR or homology modeling methods and so is the theoretical understanding of protein-ligand interactions. As such, structure-based approaches to drug-design and in silico screening are becoming routine part of most modern lead discovery programs. Prioritization of compound libraries is an extremely important task that aims at the rapid identification of tight-binding ligands and ultimately new therapeutic compounds. These in silico approaches combined with other experimental methods facilitate the design of new medicines to treat cardiovascular, degenerative, infectious, and neoplastic diseases, among others. Here, we review key concepts and specific features of several selected ligand-receptor docking/scoring methods while several other topics pertaining to the field of in silico screening are reviewed in the following articles of this special issue of Current Protein and Peptide Science.
    背景与目标: :学术界和工业界科学家发现新药的过程最近通过许多新颖而令人兴奋的技术经历了一次真正的复兴。通过使用平行化学,X射线晶体学,NMR或同源性建模方法,蛋白质结构和/或化学配体的数量不断增长,因此对蛋白质-配体相互作用的理论理解也是如此。因此,基于结构的药物设计和计算机筛查方法已成为大多数现代铅发现计划的常规组成部分。化合物库的优先级排序是一项极其重要的任务,旨在快速识别紧密结合的配体并最终鉴定出新的治疗性化合物。这些计算机模拟方法与其他实验方法相结合,有助于设计用于治疗心血管疾病,退行性疾病,传染性疾病和肿瘤性疾病等的新药。在这里,我们回顾了几种选定的配体-受体对接/计分方法的关键概念和特定特征,与此同时,本期《当前蛋白质与肽科学》特刊的以下文章回顾了与计算机筛选领域有关的其他几个主题。
  • 【通过基于对接的虚拟筛选鉴定PDZ配体,以开发新型镇痛药。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2013.02.100 复制DOI
    作者列表:Bouzidi N,Deokar H,Vogrig A,Boucherle B,Ripoche I,Abrunhosa-Thomas I,Dorr L,Wattiez AS,Lian LY,Marin P,Courteix C,Ducki S
    BACKGROUND & AIMS: :Disrupting the interaction between the PDZ protein, PSD-95, and its target ligands (such as the glutamate NMDA receptor or the serotonin 5-HT2A receptor) was found to reduce hyperalgesia in various models of neuropathic pain. Here, we set out to identify lead molecules which would interact with PSD-95, and hence, would potentially display analgesic activity. We describe the virtual screening of the Asinex and Cambridge databases which together contain almost one million molecules. Using three successive docking filters and visual inspection, we identified three structural classes of molecules and synthesized a potential lead compound from each class. The binding of the molecules with the PDZ domains of PSD-95 was assessed by (1)H-(15)N HSQC NMR experiments. The analgesic activity of the best ligand, quinoline 2, was evaluated in vivo in a model of neuropathic pain and showed promising results.
    背景与目标: :在各种神经性疼痛模型中,发现破坏PDZ蛋白,PSD-95及其靶配体(例如谷氨酸NMDA受体或血清素5-HT2A受体)之间的相互作用可减少痛觉过敏。在这里,我们着手确定将与PSD-95相互作用的铅分子,从而潜在地显示出止痛活性。我们描述了一起包含近一百万个分子的Asinex和Cambridge数据库的虚拟筛选。使用三个连续的对接过滤器和目视检查,我们确定了分子的三个结构类别,并从每个类别中合成了潜在的先导化合物。通过(1)H-(15)N HSQC NMR实验评估了分子与PSD-95的PDZ域的结合。最佳配体喹啉2的镇痛活性已在神经性疼痛模型中进行了体内评估,并显示出令人鼓舞的结果。
  • 【开发基于分子对接的结合能以预测BPA及其类似物的联合作用。】 复制标题 收藏 收藏
    DOI:10.1177/0960327110372400 复制DOI
    作者列表:Zhang HC,Hu XL,Yin DQ,Lin ZF
    BACKGROUND & AIMS: :A general proposal for predicting the joint effect of endocrine disrupting chemicals by examining binding energy models was developed in this study. 2,2-bis(4-hydroxyphenyl)propane (BPA) and 11 of its analogs were chosen, and the estrogenic activity of each compound was measured by determining its EC50 value using a recombinant gene yeast assay. Binding energies (BEs) were calculated using Surflex-Docking software. The analysis of the relationship between EC50 values and BEs showed that there is a linear correlation between the BEs and EC50 values. Furthermore, the analysis of the given binary and quaternary mixtures of BPA and three of its analogs showed that the joint effects of the mixtures were affected by the proportions of the chemicals in each mixture and their relative binding energy. The correlation between the joint effects of mixtures and the binding energy of the individual compounds has been described using one formula, which can be used to predict the joint effects of other mixtures.
    背景与目标: :这项研究提出了通过检查结合能模型来预测内分泌干扰化学物质联合作用的一般建议。选择2,2-双(4-羟苯基)丙烷(BPA)及其11种类似物,并使用重组基因酵母测定法通过测定其EC50值来测量每种化合物的雌激素活性。使用Surflex-Docking软件计算结合能(BE)。对EC50值和BEs之间关系的分析表明,BEs和EC50值之间存在线性关系。此外,对给定的BPA的二元和四元混合物及其三个类似物的分析表明,混合物的联合作用受每种混合物中化学物质的比例及其相对结合能的影响。已经使用一个公式描述了混合物的联合作用与各个化合物的结合能之间的相关性,该公式可用于预测其他混合物的联合作用。
  • 【GPCR靶标和反靶标对接筛选中的选择性挑战。】 复制标题 收藏 收藏
    DOI:10.1021/acs.jmedchem.8b00718 复制DOI
    作者列表:Weiss DR,Karpiak J,Huang XP,Sassano MF,Lyu J,Roth BL,Shoichet BK
    BACKGROUND & AIMS: :To investigate large library docking's ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D2 and serotonin 5-HT2A receptors were targeted, seeking selectivity against the histamine H1 receptor. In a second campaign, κ-opioid receptor ligands were sought with selectivity versus the μ-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D2/5-HT2A ligand with 21-fold selectivity versus the H1 receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field.
    背景与目标: :为了研究大型文库对接的能力,以发现对目标具有联合活性且对反目标具有选择性的分子,我们以多巴胺D2和5-羟色胺5-HT2A受体为目标,寻求对组胺H1受体的选择性。在第二项活动中,寻求与μ阿片受体相比具有选择性的κ阿片受体配体。尽管针对靶点的命中率介于40%至63%之间,但即使针对分子假定缺乏与靶点的结合力来选择分子,其对靶点的抵抗力也一样好。亲和力对于脱靶者通常也一样好或更好。尽管偶尔可能找到选择性分子,例如相对于H1受体具有21倍选择性的中等纳摩尔级D2 / 5-HT2A配体,但这是例外。假阴性在对接目标上的对接屏幕中是可以容忍的,而在反目标上则是不能容忍的。解决此问题可能需要该领域的新策略。

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