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Correlation between Virtual Screening Performance and Binding Site Descriptors of Protein Targets. 虚拟筛选性能与蛋白靶点结合位点描述子的相关性研究。
Pub Date : 2018-01-11 eCollection Date: 2018-01-01 DOI: 10.1155/2018/3829307
Jamal Shamsara

Rescoring is a simple approach that theoretically could improve the original docking results. In this study AutoDock Vina was used as a docked engine and three other scoring functions besides the original scoring function, Vina, as well as their combinations as consensus scoring functions were employed to explore the effect of rescoring on virtual screenings that had been done on diverse targets. Rescoring by DrugScore produces the most number of cases with significant changes in screening power. Thus, the DrugScore results were used to build a simple model based on two binding site descriptors that could predict possible improvement by DrugScore rescoring. Furthermore, generally the screening power of all rescoring approach as well as original AutoDock Vina docking results correlated with the Maximum Theoretical Shape Complementarity (MTSC) and Maximum Distance from Center of Mass and all Alpha spheres (MDCMA). Therefore, it was suggested that, with a more complete set of binding site descriptors, it could be possible to find robust relationship between binding site descriptors and response to certain molecular docking programs and scoring functions. The results could be helpful for future researches aiming to do a virtual screening using AutoDock Vina and/or rescoring using DrugScore.

重新评分是一种简单的方法,理论上可以改善原有的对接结果。本研究采用AutoDock Vina作为对接引擎,并采用除原有评分函数Vina外的其他三个评分函数及其组合作为共识评分函数,探讨评分对不同目标的虚拟筛选的影响。以DrugScore评分产生的病例数最多,筛选能力变化显著。因此,我们使用DrugScore的结果来建立一个基于两个结合位点描述符的简单模型,该模型可以通过DrugScore评分来预测可能的改善。此外,一般来说,所有评分方法的筛选能力以及原始AutoDock Vina对接结果与最大理论形状互补性(MTSC)和最大到质心和所有阿尔法球的距离(MDCMA)相关。因此,我们认为,有了更完整的结合位点描述子集,就有可能找到结合位点描述子与某些分子对接程序和评分函数的响应之间的稳健关系。这些结果可能有助于未来的研究,旨在使用AutoDock Vina进行虚拟筛选和/或使用DrugScore进行评分。
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引用次数: 11
Usefulness of Urea as a Means of Improving the Solubility of Poorly Water-Soluble Ascorbyl Palmitate. 尿素作为提高难水溶性抗坏血酸棕榈酸盐溶解度手段的有效性。
Pub Date : 2017-01-01 Epub Date: 2017-11-06 DOI: 10.1155/2017/4391078
Yutaka Inoue, Daichi Niiyama, Isamu Murata, Ikuo Kanamoto

The aim of this study was to evaluate complexes of L-ascorbyl palmitate (ASCP) and urea (UR). This evaluation involved differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), near-infrared spectroscopy (NIR), a solubility test, a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging test, and a mushroom tyrosinase inhibition assay. Physicochemical evaluation revealed that ASCP/UR complexes form at a molar ratio of 1/12. The solubility test revealed that ASCP/UR complexes had increased solubility compared to ASCP. The DPPH radical scavenging test and mushroom tyrosinase inhibition assay revealed that the activity of ASCP/UR complexes was not impaired by complex formation. These results are probably due to the tetragonal crystal system of UR changing to a hexagonal crystal system and interaction with the alkyl group of ASCP.

本研究的目的是评价l -抗坏血酸棕榈酸酯(ASCP)和尿素(UR)的复合物。该评价包括差示扫描量热法(DSC)、粉末x射线衍射(PXRD)、扫描电镜(SEM)、近红外光谱(NIR)、溶解度测试、1,1-二苯基-2-苦酰肼(DPPH)自由基清除测试和蘑菇酪氨酸酶抑制测试。理化评价表明ASCP/UR配合物形成的摩尔比为1/12。溶解度试验表明,ASCP/UR配合物的溶解度比ASCP高。DPPH自由基清除试验和蘑菇酪氨酸酶抑制试验表明,ASCP/UR复合物的活性不受复合物形成的影响。这些结果可能与UR的四方晶系转变为六方晶系以及与ASCP的烷基相互作用有关。
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引用次数: 5
Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs. 利用噻唑烷二酮靶向过氧化物酶体增殖物激活受体:新型降糖药的设计策略。
Pub Date : 2017-01-01 Epub Date: 2017-06-05 DOI: 10.1155/2017/1069718
Neelaveni Thangavel, Mohammed Al Bratty, Sadique Akhtar Javed, Waquar Ahsan, Hassan A Alhazmi

Thiazolidinediones are a class of well-established antidiabetic drugs, also named as glitazones. Thiazolidinedione structure has been an important structural domain of research, involving design and development of new drugs for the treatment of type 2 diabetes. Extensive research on the mechanism of action and the structural requirements has revealed that the intended antidiabetic activity in type 2 diabetes is due to their agonistic effect on peroxisome proliferator-activated receptor (PPAR) belonging to the nuclear receptor super family. Glitazones have specific affinity to PPARγ, one of the subtypes of PPARs. Certain compounds under development have dual PPARα/γ agonistic activity which might be beneficial in obesity and diabetic cardiomyopathy. Interesting array of hybrid compounds of thiazolidinedione PPARγ agonists exhibited therapeutic potential beyond antidiabetic activity. Pharmacology and chemistry of thiazolidinediones as PPARγ agonists and the potential of newer analogues as dual agonists of PPARs and other emerging targets for the therapy of type 2 diabetes are presented. This review highlights the possible modifications of the structural components in the general frame work of thiazolidinediones with respect to their binding efficacy, potency, and selectivity which would guide the future research in design of novel thiazolidinedione derivatives for the management of type 2 diabetes.

噻唑烷二酮类药物是一类公认的抗糖尿病药物,也被称为格列酮。噻唑烷二酮结构一直是一个重要的结构研究领域,涉及到治疗2型糖尿病新药的设计和开发。对其作用机制和结构要求的广泛研究表明,2型糖尿病的预期降糖活性是由于它们对核受体超家族的过氧化物酶体增殖物激活受体(PPAR)的激动作用。格列酮对ppar亚型之一的PPARγ具有特异性亲和力。某些正在开发的化合物具有双重PPARα/γ激动活性,可能对肥胖和糖尿病性心肌病有益。一系列有趣的噻唑烷二酮类PPARγ激动剂的杂化化合物显示出除抗糖尿病活性外的治疗潜力。本文介绍了噻唑烷二酮类药物作为PPARγ激动剂的药理学和化学性质,以及新型类似物作为PPARγ双重激动剂和其他新兴靶点治疗2型糖尿病的潜力。本文综述了噻唑烷二酮类药物在结合功效、效力和选择性方面可能存在的结构成分的修饰,这将指导未来设计用于治疗2型糖尿病的新型噻唑烷二酮衍生物的研究。
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引用次数: 58
Design, Synthesis, and Cytotoxicity Evaluation of Novel Griseofulvin Analogues with Improved Water Solubility. 新型水溶性灰黄霉素类似物的设计、合成及细胞毒性评价。
Pub Date : 2017-01-01 Epub Date: 2017-12-07 DOI: 10.1155/2017/7386125
Ahmed K Hamdy, Mahmoud M Sheha, Atef A Abdel-Hafez, Samia A Shouman

Griseofulvin 1 is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Study of SAR of some griseofulvin analogues has led to the identification of 2'-benzyloxy griseofulvin 3, a more potent analogue which retards tumor growth through inhibition of centrosomal clustering. However, similar to griseofulvin 1, compound 3 exhibited poor aqueous solubility. In order to improve the poor water solubility, six new griseofulvin analogues 5-10 were synthesized and tested for their antiproliferative activity and water solubility. The semicarbazone 9 and aminoguanidine 10 analogues were the most potent against HCT116 and MCF-7 cell lines. In combination studies, compound 9 was found to exert synergistic effects with tamoxifen and 5-fluorouracil against MCF-7 and HCT116 cells proliferation, respectively. The flow cytometric analysis of effect of 9 on cell cycle progression revealed G2/M arrest in HCT116. In addition, compound 9 induced apoptosis in MCF-7 cells. Finally, all synthesized analogues revealed higher water solubility than griseofulvin 1 and benzyloxy analogue 3 in pH 1.2 and 6.8 buffer solutions.

灰黄霉素1是一种重要的抗真菌药物,近年来因其对哺乳动物癌细胞的抗增殖作用而受到关注。一些灰黄霉素类似物的SAR研究导致鉴定出2'-苯氧基灰黄霉素3,这是一种更有效的类似物,通过抑制中心体聚集来延缓肿瘤生长。然而,与灰黄霉素1类似,化合物3表现出较差的水溶性。为了改善灰黄霉素水溶性差的问题,合成了6个新的灰黄霉素类似物5-10,并对其抗增殖活性和水溶性进行了测试。缩氨基脲9和氨基胍10类似物对HCT116和MCF-7细胞系最有效。在联合研究中发现,化合物9与他莫昔芬和5-氟尿嘧啶分别对MCF-7和HCT116细胞增殖具有协同作用。流式细胞术分析9对细胞周期进程的影响显示HCT116中G2/M阻滞。此外,化合物9可诱导MCF-7细胞凋亡。最后,所有合成的类似物在pH为1.2和6.8的缓冲溶液中的水溶性均高于灰黄霉素1和苯氧基类似物3。
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引用次数: 5
Synthesis, Antimicrobial, and Computational Evaluation of Novel Isobutylchalcones as Antimicrobial Agents. 新型异丁基查尔酮抗菌药物的合成、抗菌及计算评价。
Pub Date : 2017-01-01 Epub Date: 2017-12-26 DOI: 10.1155/2017/6873924
Afzal Basha Shaik, Rajendra Prasad Yejella, Shahanaaz Shaik

A series of 25 new chalcones were synthesized by Claisen-Schmidt condensation, well characterized by spectroscopic data, and evaluated for their antibacterial and antifungal activities by serial tube dilution method. Among the compounds tested, A3 and A6 containing 2,4-dichlorophenyl and 2,4-difluorophenyl moiety, respectively, were found to be the most potent in the series against both bacterial and fungal strains with a MIC value of 16 µg/mL in each case. Further computational evaluation for antimicrobial activity was performed by atom based 3D-QSAR using PHASE™ software in order to have a correlation between the observed activities and predicted activities. The computational studies were in agreement with the in vitro antimicrobial results and had identified the most promising chalcones as antimicrobial agents and the responsible structural features for the proposed activity.

采用Claisen-Schmidt缩合法合成了25个新查尔酮,通过光谱数据对其进行了表征,并通过连续管稀释法对其抑菌和抗真菌活性进行了评价。在所测试的化合物中,含有2,4-二氯苯基和2,4-二氟苯基片段的A3和A6分别被发现对细菌和真菌菌株最有效,每种情况下的MIC值均为16µg/mL。利用PHASE™软件,通过基于原子的3D-QSAR对抗菌活性进行进一步的计算评估,以便在观察到的活性和预测的活性之间建立相关性。计算研究与体外抗菌结果一致,并确定了最有希望作为抗菌剂的查尔酮及其活性的相关结构特征。
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引用次数: 10
Fluorinated Adenosine A2A Receptor Antagonists Inspired by Preladenant as Potential Cancer Immunotherapeutics. 受前驱体启发的氟化腺苷A2A受体拮抗剂作为潜在的癌症免疫治疗药物。
Pub Date : 2017-01-01 Epub Date: 2017-10-19 DOI: 10.1155/2017/4852537
Gengyang Yuan, Tanner C Jankins, Christopher G Patrick, Phaethon Philbrook, Olivia Sears, Stephen Hatfield, Michail Sitkovsky, Neil Vasdev, Steven H Liang, Mary Jo Ondrechen, Michael P Pollastri, Graham B Jones

Antagonism of the adenosine A2A receptor on T cells blocks the hypoxia-adenosinergic pathway to promote tumor rejection. Using an in vivo immunoassay based on the Concanavalin A mouse model, a series of A2A antagonists were studied and identified preladenant as a potent lead compound for development. Molecular modeling was employed to assist drug design and subsequent synthesis of analogs and those of tozadenant, including fluorinated polyethylene glycol PEGylated derivatives. The efficacy of the analogs was evaluated using two in vitro functional bioassays, and compound 29, a fluorinated triethylene glycol derivative of preladenant, was confirmed as a potential immunotherapeutic agent.

T细胞上腺苷A2A受体的拮抗作用阻断缺氧-腺苷能通路,促进肿瘤排斥反应。利用基于Concanavalin A小鼠模型的体内免疫分析,研究了一系列A2A拮抗剂,并确定了preladenant是一种有效的促进发育的先导化合物。采用分子模型来辅助药物设计和随后的类似物和毒腺剂的合成,包括氟化聚乙二醇聚乙二醇衍生物。使用两种体外功能生物测定法评估了类似物的功效,并确认化合物29 (preladenant的氟化三甘醇衍生物)是一种潜在的免疫治疗剂。
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引用次数: 9
Biophysical Approaches Facilitate Computational Drug Discovery for ATP-Binding Cassette Proteins. 生物物理方法促进atp结合盒蛋白的计算药物发现。
Pub Date : 2017-01-01 Epub Date: 2017-03-19 DOI: 10.1155/2017/1529402
Steven V Molinski, Zoltán Bozóky, Surtaj H Iram, Saumel Ahmadi

Although membrane proteins represent most therapeutically relevant drug targets, the availability of atomic resolution structures for this class of proteins has been limited. Structural characterization has been hampered by the biophysical nature of these polytopic transporters, receptors, and channels, and recent innovations to in vitro techniques aim to mitigate these challenges. One such class of membrane proteins, the ATP-binding cassette (ABC) superfamily, are broadly expressed throughout the human body, required for normal physiology and disease-causing when mutated, yet lacks sufficient structural representation in the Protein Data Bank. However, recent improvements to biophysical techniques (e.g., cryo-electron microscopy) have allowed for previously "hard-to-study" ABC proteins to be characterized at high resolution, providing insight into molecular mechanisms-of-action as well as revealing novel druggable sites for therapy design. These new advances provide ample opportunity for computational methods (e.g., virtual screening, molecular dynamics simulations, and structure-based drug design) to catalyze the discovery of novel small molecule therapeutics that can be easily translated from computer to bench and subsequently to the patient's bedside. In this review, we explore the utility of recent advances in biophysical methods coupled with well-established in silico techniques towards drug development for diseases caused by dysfunctional ABC proteins.

尽管膜蛋白代表了大多数治疗相关的药物靶点,但这类蛋白的原子分辨率结构的可用性受到限制。这些多体转运体、受体和通道的生物物理性质阻碍了结构表征,而最近体外技术的创新旨在减轻这些挑战。其中一类膜蛋白,atp结合盒(ABC)超家族,在整个人体中广泛表达,是正常生理和突变时致病所必需的,但在蛋白质数据库中缺乏足够的结构表示。然而,最近生物物理技术的改进(例如,冷冻电子显微镜)使得以前“难以研究”的ABC蛋白能够以高分辨率进行表征,从而深入了解分子作用机制以及揭示治疗设计的新药物位点。这些新的进展为计算方法(例如,虚拟筛选,分子动力学模拟和基于结构的药物设计)提供了充足的机会,以催化发现新的小分子疗法,这些疗法可以很容易地从计算机转化为实验台,随后转化为患者的床边。在这篇综述中,我们探讨了生物物理方法的最新进展以及成熟的计算机技术对由功能失调的ABC蛋白引起的疾病的药物开发的应用。
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引用次数: 6
New Conjugates of Quinoxaline as Potent Antitubercular and Antibacterial Agents 喹诺啉的新结合物作为有效的抗结核和抗菌药物
Pub Date : 2016-03-08 DOI: 10.1155/2016/6471352
R. Peraman, R. Kuppusamy, Sunil Kumar Killi, Y. P. Reddy
Considering quinoxaline as a privileged structure for the design of potent intercalating agents, some new sugar conjugates of quinoxaline were synthesized and characterized by IR, 1HNMR, 13C NMR, and mass spectral data. In vitro testing for antitubercular and antimicrobial activities was performed against Mycobacterium tuberculosis H 37 Rv and some pathogenic bacteria. Results revealed that conjugate containing ribose moiety demonstrated the most promising activity against Mycobacteria and bacteria with minimum inhibitory concentrations (MIC) of 0.65 and 2.07 μM, respectively. Other conjugates from xylose, glucose, and mannose were moderately active whilst disaccharides conjugates were found to be less active. In silico docking analysis of prototype compound revealed that ATP site of DNA gyrase B subunit could be a possible site for inhibitory action of these synthesized compounds.
考虑到喹啉是设计强插层剂的有利结构,合成了一些新的喹啉糖偶联物,并通过IR、1HNMR、13C NMR和质谱数据对其进行了表征。对结核分枝杆菌h37rv和部分致病菌进行了体外抗结核和抗菌活性试验。结果表明,含有核糖片段的缀合物对分枝杆菌和细菌的最低抑制浓度(MIC)分别为0.65 μM和2.07 μM,具有较好的抑制活性。木糖、葡萄糖和甘露糖的其他偶联物具有中等活性,而双糖偶联物活性较低。原型化合物的硅对接分析表明,DNA回转酶B亚基的ATP位点可能是这些合成化合物抑制作用的可能位点。
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引用次数: 21
Changes in the Physicochemical Properties of Piperine/β-Cyclodextrin due to the Formation of Inclusion Complexes 包合物形成对胡椒碱/β-环糊精理化性质的影响
Pub Date : 2016-02-22 DOI: 10.1155/2016/8723139
Toshinari Ezawa, Y. Inoue, Sujimon Tunvichien, Rina Suzuki, I. Kanamoto
Piperine (PP) is a pungent component in black pepper that possesses useful biological activities; however it is practically insoluble in water. The aim of the current study was to prepare a coground mixture (GM) of PP and β-cyclodextrin (βCD) (molar ratio of PP/βCD = 1/1) and subsequently evaluate the solubility of PP and physicochemical properties of the GM. DSC thermal behavior of the GM showed the absence of melting peak of piperine. PXRD profile of the GM exhibited halo pattern and no characteristic peaks due to PP and βCD were observed. Based on Job's plot, the PP/βCD complex in solution had a stoichiometric ratio of 1/1. Raman spectrum of the GM revealed scattering peaks assigned for the benzene ring (C=C), the methylene groups (CH2), and ether groups (C-O-C) of PP that were broaden and shifted to lower frequencies. SEM micrographs showed that particles in the GM were agglomerated and had rough surface, unlike pure PP and pure βCD particles. At 15 min of dissolution testing, the amount dissolved of PP in the GM was dramatically increased (about 16 times) compared to that of pure PP. Moreover the interaction between PP and βCD cavity was detected by 1H-1H NMR nuclear Overhauser effect spectroscopy NMR spectroscopy.
胡椒碱(PP)是黑胡椒中的一种刺激性成分,具有有益的生物活性;然而,它几乎不溶于水。本研究的目的是制备PP和β-环糊精(β - cd)的共混物(GM) (PP/βCD的摩尔比为1/1),随后评价了PP的溶解度和GM的理化性质。GM的DSC热行为显示没有胡椒碱的熔化峰。GM的PXRD谱表现为光晕型,未见PP和βCD的特征峰。根据Job图,溶液中PP/β - cd配合物的化学计量比为1/1。聚丙烯的拉曼光谱显示苯环(C=C)、亚甲基(CH2)和醚基(C- o -C)的散射峰变宽并移至较低的频率。SEM显微图显示,与纯PP和纯βCD颗粒不同,GM颗粒呈团聚状,表面粗糙。溶解测试15 min时,PP在GM中的溶解量较纯PP显著增加(约16倍),并通过1H-1H NMR核奥弗豪瑟效应谱检测PP与βCD空腔的相互作用。
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引用次数: 31
Design and Microwave Assisted Synthesis of Coumarin Derivatives as PDE Inhibitors 香豆素类PDE抑制剂的设计与微波辅助合成
Pub Date : 2016-02-21 DOI: 10.1155/2016/9890630
M. Kumbar, R. Kamble, A. Kamble, S. R. Salian, S. Kumari, Ramya Nair, G. Kalthur, S. Adiga, D. J. Prasad
Coumarins appended to benzimidazole through pyrazole are designed and synthesized using microwave irradiation. These compounds were analyzed for phosphodiesterase (PDE) inhibition indirectly by motility pattern in human spermatozoa. Some of the synthesized compounds, namely, 5d, 5e, 5f, 5g, 5h, and 5k, have exhibited potent inhibitory activity on PDE.
采用微波辐照法,通过吡唑对苯并咪唑进行了香豆素的设计与合成。通过精子运动模式间接分析了这些化合物对磷酸二酯酶(PDE)的抑制作用。合成的部分化合物5d、5e、5f、5g、5h、5k对PDE表现出较强的抑制活性。
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引用次数: 10
期刊
International Journal of Medicinal Chemistry
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