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Pharmacophore Mapping and Docking on Triazepane Derivatives as DPP-IV Inhibitors
Patil Swaraj 1*,Gurjar Sonam 2,Khodre Suraj 3,Khodre Jyoti 4
International Journal of Research in Pharmacy and Science , 2012,
Abstract: The molecule is inserted on the workspace of the Ligand scout 3.30b trial version. Energy was minimized by MMFF94 and pharmacophore part of compound is created which shows the hydrogen bonding, hydrophobic bonding and aromatic environment. Pharmacophore mapping shows hydrogen bond, hydrophobic bonding and aromatic hydrogen. The pdb (2OLE) of protein, ligand and reference (vildagliptin) is inserted on the workspace of the Molegro virtual docker 5.0 trial. Preparation of protein as well as ligand done, create surface area of protein, detection of cavity. The reference compound taken in docking is vildagliptin. The parameter selected in the docking studies were moldock optimizer, number of runs 10, population size 50, cross over rate 0.90 and max iteration 2000 and cavity selected is user define. Docking studies help in checking the interaction between protein and the ligand, interaction shows in docking are Glu 205, Arg 125, Gly 741, Trp 629, Ala 654, Asn 710, Asp 708, Val 711, His 740. The derivatives prepared by after docking and pharmacophore mapping helps in creating a most potent compound.
Pharmacophore Mapping, Docking and Three Dimensional QSAR Analysis of [(S)- γ -(Arylamino) Prolyl] Thiazolidine Compounds As A Potent and Stable DPP-IV Inhibitors  [PDF]
Sharma Rajesh,Patil Swaraj
International Journal of Research in Pharmacy and Science , 2013,
Abstract: Novel DPP-IV (Dipeptidyl peptidase-IV) inhibitors were designed based on a previously describedseries diabetes. Despite years of continual efforts, diabetes is still one of the most dangerous diseases inthe world. The enzyme which increases the level of glucose in the body is DPP-IV. Inhibition of DPPIVis currently explored as a novel therapy for treatment of type 2 diabetes. In view of that we haveattempt to design a novel DP-IV inhibiting agents through molecular modeling. Essentialpharmacophoric feature were identified using ligand Scout. The common pharmacophoric featureswere identified by Pharmacophore mapping, three pharmacophoric sites were found to be hydrogenbond acceptor and other two were hydrogen bond donor. Pharmacophoric feature is shown by colorcoding. In addition docking study was also performed using Molegro 5.0, to establish theoretical drugreceptor interaction between ligands and DPP-IV enzyme. It was found that all the ligands formed ahydrogen bond interaction with His 740 of DPP-IV enzyme. The unbound His 740 is essential for theinhibition of DPP-IV enzyme The multi parameter 3D QSAR models have also generated, describedrelationship of DPP-IV inhibitory activity and physiochemical parameters, result can be used forstructure optimization. Among several 3D QSAR model, two models with good statistical values wereselected. Activity of model 1 and model 2 with good correlation coefficient was (0.6357 and 0.8470)and internal predictivity was (0.9744 and 0.6741). The results are promising and can be used to designnovel DPP-IV inhibiting agents.
基于结构和药效团特征的人类腺苷受体拮抗剂选择性比较
Comparison of the Selectivity of Human Adenosine Receptor Antagonists Based on Structure and Pharmacophore Features
 [PDF]

曾凌晓,李欣然,金宏威,刘振明(),张亮仁()
- , 2015, DOI: 10.3866/PKU.WHXB201505253
Abstract: 腺苷受体是重要的治疗靶标,选择性腺苷受体拮抗剂具有广泛的临床应用前景.本文通过同源模建构建了腺苷A1、A2B和A3受体的结构,采用LigandScout 3.12软件分别构建了腺苷受体四种亚型的拮抗剂药效团模型.然后利用Schr?dinger程序中的Induced Fit Docking模块完成受体-拮抗剂结合模式的预测,并与药效团结果进行比对.结果发现,由于结合口袋部位的残基在家族间高度保守,模建得到的各个亚型受体的初始结构活性口袋部位极为相似,无法用于亚型选择性拮抗剂的识别.而腺苷受体四种亚型拮抗剂药效团的药效特征与空间排布都不同,并与以前突变实验信息相吻合.研究结果说明,结合口袋部位的优化是模建中的关键步骤,基于配体的药效团模型所包含的一系列药效特征元素如氢键受体、氢键供体、疏水基团、芳环中心,可以很好地表征受体结合部位氢键、疏水空腔的位置及其方向.本文研究结果可以为进一步的优化同源模建结果,寻找新型的人类腺苷受体选择性拮抗剂提供理论依据.
Adenosine receptors (ARs) are crucial therapeutic targets, and selective adenosine receptor antagonists are promising for numerous therapeutic applications. In this study, three dimensional models of human adenosine A1, A2B, and A3 receptors (A1AR, A2BAR, A3AR, respectively) were generated by homology modeling. In addition, pharmacophore models of the antagonists of four human adenosine receptor subtypes were developed using the LigandScout 3.12 program. Furthermore, Induced Fit Docking module of Schr?dinger program was implemented to investigate receptor-ligand interactions. The results show that because of the subfamily-wide conservation of the core pocket residues, the ligand binding pockets of the three raw AR homology models are extremely similar, which poses challenges for subtype selective ligand recognition. However, the pharmacophore models of the four AR subtypes differ in pharmacophore features and spatial configuration, which are also consistent with previous site-directed mutagenesis studies. This indicates that binding site optimization is a crucial step in model generation, and the distributions for a set of pharmacophore features in ligand-based pharmacophore, including hydrogen bond acceptors, hydrogen bond donors, hydrophobic centroids, and aromatic rings, can reflect the position and direction characterization of hydrogen bonds and hydrophobic cavities, which aid identification and characterization of binding sites. This study may provide a significant theoretical foundation for further raw model optimization in homology modeling and discovery of novel selective human adenosine receptor antagonists
Application of Pharmacophore Technique in the Study of Effective Substance of Chinese Medicinals
药效团技术在中药药效成分研究中的应用

Wang Xing,Zhang Yanling,Qiao Yanjiang,
王星
,张燕玲,乔延江

世界科学技术-中医药现代化 , 2012,
Abstract: The effective substance of Chinese medicinals has been a focus of traditional Chinese medicine (TCM) studies for long time. With the application of pharmacophore-based 3D structure database searching in the discovery and optimization of lead compounds for drug design, the pharmacophore technology has gradually caught attention in modern TCM studies in recent years. In this paper, the progress of pharmacophore methods was used. The application of pharmacophore methods in the Active Clusters of Traditional Chinese Medicine(AC-TCM) identification, targets searching, action of TCM on metabolic enzymes and the study in the properties of TCM was reviewed. Also problems, strategy and prospect of pharmacophore in the study of TCM were discussed.
VR+药效团:一种交互可视的虚拟筛选系统
VR + Pharmacophore: an Interactive and Visual Virtual Screening System
 [PDF]

何高奇,龚博杰,陈诚,郁明强,卢兴见,李洪林
- , 2018,
Abstract: 基于药效团的虚拟筛选技术比传统筛选技术具有更高的准确率、更快的计算速度和更低的研究成本。但分子的微观性和结构复杂性对用户的空间感知和数据分析能力提出了挑战。本文将虚拟现实和药效团计算技术相结合,基于Unity3D引擎和HTC Vive设备,设计实现了一个交互可视的虚拟筛选系统,主要功能包括分子解析和绘制、药效团计算、基于HTC Vive的可视交互。实验表明本文提出的交互可视虚拟筛选系统能够为药效团的设计分析带来了新的视角,增强了药物设计研究者的交互体验。
Pharmscophore-based virtual screening technology had higher accuracy rate, faster calculation speed and lower research cost than traditional screening technology. However, the microscopic and struectural complexity of the molecule posed a challenge to the user’s spatial perception and data analysis capabilities. In this paper, the virtual reality and pharmacophore computing technologywere combined design to interactive visual virtual screening system based on Unity 3D engine and HTC Vive device. The main functions of the system included molecular analysis and rendering, pharmacophore calculation, visual interaction.based on HTC Vice. Experiments showed that the interactive visual virtual screening system proposed in this paper could bring a new perspective for the design of pharmacophor and enhance the interaction experience of drug design researchers.
Build a Pharmacophore Model of HMG-CoA Reductase Inhibitors Using Distance Comparison Method
距离比较法构建HMG—CoA还原酶抑制剂药效团

Cui Jianhu,Zhang Yanling,Qiao Yanjiang,
崔建华
,张燕玲,乔延江

世界科学技术-中医药现代化 , 2008,
Abstract: Author discussed the impacts of different reference structures on building a pharmacophore model of HMG-CoA reductase inhibitors using DIStance COmparison method (DISCO).In the study,13 inhibitors with the pharmacological activity of rat liver cells were obtained from the MDDR database as the training set.Three dimensional pharmacophore models were developed using DISCO.Six high active compounds were selected as reference structures respectively. The results models were evaluated by Compare Molecule Field A...
Pharmacophore Model Generation of ETB Inhibitors
ETB受体拮抗剂三维药效团的构建

Yang Zhen,Zhang Yanling,Qiao Yanjiang,
杨珍
,张燕玲,乔延江

世界科学技术-中医药现代化 , 2012,
Abstract: 本文以对在CHO细胞中表达的人类ETB受体有拮抗作用的28个化合物为训练集,利用Catalyst计算所得ETB受体拮抗剂的最优药效团模型由两个氢键受体、一个芳环基团和一个疏水基团组成。最优模型的Fixed cost、Total cost和△Cost值分别为114.792、136.967和38.081。训练集化合物活性的实测值与预测值相关系数为0.870,偏差值为1.198,有效活性命中率A%和综合评价指数CAI值分别为84%和2.389。该模型对测试集化合物也有较好的预测能力,所命中测试集化合物的实际活性值和预测活性值的线性相关系数为0.736。研究结果表明所构建的药效团模型具有一定的可靠性,可以用来进行数据库的搜索,寻找新型的ETB受体拮抗剂。
Pharmacophore Model Generation of Thrombin Inhibitors  [PDF]
Xing Wang, Yanling Zhang, Yuhong Xiang, Zhenzhen Ren, Yanjiang Qiao
Journal of Software Engineering and Applications (JSEA) , 2012, DOI: 10.4236/jsea.2012.512B017
Abstract: Thrombin, an important factor of clotting system, take part in a variety of physiological actions, such as blood clotting, anticoagulation, thrombosis and fibrinolysis. Inhibiting thrombin is a pivotal and effective step for the prophylaxis of venous and arterial thrombosis, as well as prevent myocardial infarction for high-risk patients. In this study, a three dimensional pharmacophore model was generated for the molecules which are responsible for vasodilation activities targeting thrombin. Ten compounds with known thrombin-inhibiting activity values were selected as training set to generate the hypothesis using GALAHAD program in SYBYL 7.0 software. The best hypothesis comprises five pharmacophore features: four hydrophobes groups and one positively charged group. It has been further validated towards a test set including known activity compounds obtained from Binding Database, the values of effectively active hit A% and comprehensive evaluation index CAI are respectively 63.33% and 2.34, the pharmacophore was proven to be successful in discriminating active and inactive inhibitors.  Furthermore, the pharmacophore model was used as a 3D query to screen TCMD (Version 2009) database and 6 hit compounds of higher predicted activity were the reported cardiovascular activities, which may be useful for further study.
HOMOLOGY MODELING AND MOLECULAR DOCKING STUDIES OF HUMAN DPP8 AND DPP9  [cached]
S. Janardhan
International Journal of Pharmaceutical Research and Development , 2011,
Abstract: The development of potent, selective and orally bioactive Dipeptidyl Peptidase IV (DPP4) inhibitors is the real challenge for the treatment of type II diabetes mellitus. Several DPP4 inhibitors are in last-stage of clinical trials, however potential side effects are associated with them may results from other prolyldipeptidases of DPP4 include DPP8 and DPP9. Currently, the crystal structure of DPP4 is available, which is used to build homology models of DPP8 and DPP9 to understand the key residues in their active site for the design of selective DPP4 inhibitors. Further, the docking studies have been performed with potent, selective DPP4 inhibitors such as Sitagliptin, Saxagliptin and Vildagliptin with the aim of explaining the differences in activity and selectivity.
Formation of the Long Range Dpp Morphogen Gradient  [PDF]
Gerald Schwank,Sascha Dalessi,Schu-Fee Yang,Ryohei Yagi,Aitana Morton de Lachapelle,Markus Affolter,Sven Bergmann,Konrad Basler
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001111
Abstract: The TGF-β homolog Decapentaplegic (Dpp) acts as a secreted morphogen in the Drosophila wing disc, and spreads through the target tissue in order to form a long range concentration gradient. Despite extensive studies, the mechanism by which the Dpp gradient is formed remains controversial. Two opposing mechanisms have been proposed: receptor-mediated transcytosis (RMT) and restricted extracellular diffusion (RED). In these scenarios the receptor for Dpp plays different roles. In the RMT model it is essential for endocytosis, re-secretion, and thus transport of Dpp, whereas in the RED model it merely modulates Dpp distribution by binding it at the cell surface for internalization and subsequent degradation. Here we analyzed the effect of receptor mutant clones on the Dpp profile in quantitative mathematical models representing transport by either RMT or RED. We then, using novel genetic tools, experimentally monitored the actual Dpp gradient in wing discs containing receptor gain-of-function and loss-of-function clones. Gain-of-function clones reveal that Dpp binds in vivo strongly to the type I receptor Thick veins, but not to the type II receptor Punt. Importantly, results with the loss-of-function clones then refute the RMT model for Dpp gradient formation, while supporting the RED model in which the majority of Dpp is not bound to Thick veins. Together our results show that receptor-mediated transcytosis cannot account for Dpp gradient formation, and support restricted extracellular diffusion as the main mechanism for Dpp dispersal. The properties of this mechanism, in which only a minority of Dpp is receptor-bound, may facilitate long-range distribution.
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