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1.
Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q2 (cross-validated correlation coefficient) = 0.557, R2ncv (non-cross-validated correlation coefficient) = 0.740, R2pre (predicted correlation coefficient) = 0.749 and Q2 = 0.598, R2ncv = 0.767, R2pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.  相似文献   
2.
Aromatase inhibitors are the most important targets in treatment of estrogen-dependent cancers. In order to search for potent steroidal aromatase inhibitors (SAIs) with lower side effects and overcome cellular resistance, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of SAIs to build 3D QSAR models. The reliable and predictive CoMFA and CoMSIA models were obtained with statistical results (CoMFA: q2 = 0.636, r2ncv = 0.988, r2pred = 0.658; CoMSIA: q2 = 0.843, r2ncv = 0.989, r2pred = 0.601). This 3D QSAR approach provides significant insights that can be used to develop novel and potent SAIs. In addition, Genetic algorithm with linear assignment of hypermolecular alignment of database (GALAHAD) was used to derive 3D pharmacophore models. The selected pharmacophore model contains two acceptor atoms and four hydrophobic centers, which was used as a 3D query for virtual screening against NCI2000 database. Six hit compounds were obtained and their biological activities were further predicted by the CoMFA and CoMSIA models, which are expected to design potent and novel SAIs.  相似文献   
3.
Mitogen-activated protein kinase-activated protein kinase 2 (MK-2) has been identified as a drug target for the treatment of inflammatory diseases. Currently, a series of thiourea analogs as potent MK-2 inhibitors were studied using comprehensive computational methods by 3D-QSAR, molecular docking and molecular dynamics simulations for a further improvement in activities. The optimal 3D models exhibit high statistical significance of the results, especially for the CoMFA results with r(2) (ncv), q(2) values of 0.974, 0.536 for the internal validation, and r(2) (pred), r(2) (m) values of 0.910, 0.723 for the external validation and Roy's index, respectively. In addition, more rigorous validation criteria suggested by Tropsha were also employed to check the built models. Graphic representation of the results, as contoured 3D coefficient plots, also provides a clue to the reasonable modification of molecules: (i) The substituent with a bulky size and electron-rich group at the C5 position of the pyrazine ring is required to enhance the potency; (ii) The H-bond acceptor group in the C3 position of the pyrazine ring is likely to be helpful to increase MK-2 inhibition; (iii) The small and electropositive substituent as a hydrogen bond donor of the C2 position in the oxazolone ring is favored; In addition, several important amino acid residues were also identified as playing an important role in MK-2 inhibition. The agreement between 3D-QSAR, molecular docking and molecular dynamics simulations also proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential MK-2 inhibitors.  相似文献   
4.
Janus kinase 2 (JAK2) is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family of kinases, which play an important role in survival, proliferation, and differentiation of a variety of cells. JAK2 inhibitors are potential drugs for the treatment of myeloproliferative neoplasms. The three dimensional quantitative structure-activity relationships have been studied on a series of JAK2 inhibitors by comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA). The CoMFA model had a cross-validated coefficient q2 of 0.633, and the relation non-cross-validated coefficient r2 of 0.976. The F value is 225.030. The contributions of steric and electrostatic fields to the activity are 55.2% and 44.8%, respectively. For the CoMSIA study, the q2, r2, and F values of the model are 0.614, 0.929, and 88.771, respectively. The contributions of steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond donor fields to the activity are 27.3%, 23.9%, 16.4%, 21.7%, and 10.7%, respectively. The CoMFA and CoMSIA models showed strong predictive ability, and the 3D contour plots give the basis on the structure modification of JAK2 inhibitors.  相似文献   
5.
The growth and metastasis of solid tumors is dependent on angiogenesis. The vascular endothelial growth factor (VEGF) and its cell surface receptor in human KDR (kinase domain containing receptor or VEGFR-2) have particular interest because of their importance in angiogenesis. The development of novel inhibitors of VEGFR-2 would be helpful to check the growth of tumors. Quantitative structure activity relationship (QSAR) analyses used to understand the structural factors affecting inhibitory potency of thiazole-substituted pyrazolone derivatives. Several pharmacophore-based models indicated the importance of steric, hydrophobic and hydrogen bond acceptor groups to inhibitory activity. The comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analyses (CoMSIA) based 3D-QSAR models were derived using pharmacophore-based alignment. Both CoMFA (q2 = 0.70, r2 = 0.97 and ) and CoMSIA (q2 = 0.54, r2 = 0.82 and ) gave reasonable results. The molecular docking (receptor-guided technique) with a recently reported receptor structure (PDB = 1YWN) were performed. The docked alignment was subsequently used for 3D-QSAR (CoMFA; q2 = 0.56, r2 = 0.97, , CoMSIA; q2 = 0.58 r2 = 0.91, ). The overall both studies were indicated, steric, electrostatic and hydrogen bond acceptor effects contribute to the inhibitory activity. CoMFA and CoMSIA models suggested that a positive bulk with hydrophobic effect is desirable around position 4 and 5 and hydrogen bond acceptor groups around pyrazolones ring will be helpful.  相似文献   
6.
用比较分子力场分析(CoMFA)法和比较分子相似性指数分析(CoMSIA)法,建立N,N-二甲基-2-溴苯乙胺类化合物的3D—QSAR模型。CoMFA模型中,其交叉验证系数q^2=0.792,传统的相关系数R^2=0.955(R=0.978),相应立体场贡献为77.4%、静电场贡献为22.6%,优于文献的报导。CoMSIA研究中,其交叉验证系数q^2=0.757,传统的相关系数R^2=0.917(R=0.958),其疏水场、立体场、静电场贡献依次为:42.9%、39.5%、17.6%。用两种模型分别预测检测集分子的活性,结果与实验值较吻合。说明所建的模型具有较好的预测能力。通过分析CoMFA分子场等值线图,可为优化N,N-二甲基-2-溴苯乙胺类衍生物的结构提供理论指导。  相似文献   
7.
苯并呋喃类组胺H_3受体拮抗剂的构效关系研究   总被引:1,自引:0,他引:1  
绢胺H3受体在体内参与调节很多神经递质的释放.人们预期,H3受体拮抗剂将临床应用于老年性痴呆症、抑郁症、精神分裂症等中枢性疾病.本文使用三维定量构效关系研究方法,包括比较分子场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA),研究芳基苯并呋喃类H3受体拮抗剂的分子结构与生物活性之间的定量关系.本文使用CoMSIA法所获建三维定量构效关系模型,其交叉验证系数q2为0.646,非交叉验证相关系数R2为0.920,表明模型预测能力较好,同时使用"留八法"证实模型的稳定和可靠.模型中各分子场的贡献为:立体场10.4%、静电场56.9%和疏水场32.7%.三维系数等势图和静电势图显示:母核3'和4'位上的取代基对活性影响较大,估计它们是配体与受体作用的位点.本研究结果可为设计和开发活性更高的该类拮抗剂提供理论参考.  相似文献   
8.
A three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs binding a monoclonal antibody (MAb(SMR)) produced against sulfamerazine was carried out by Distance Comparison (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA). The affinities of the MAb(SMR), expressed as Log(10)IC(50), for 17 sulfonamide analogs were determined by competitive fluorescence polarization immunoassay (FPIA). The results demonstrated that the proposed pharmacophore model containing two hydrogen-bond acceptors, two hydrogen-bond donors and two hydrophobic centers characterized the structural features of the sulfonamides necessary for MAb(SMR) binding. Removal of two outliers from the initial set of 17 sulfonamide analogs improved the predictability of the models. The 3D-QSAR models of 15 sulfonamides based on CoMFA and CoMSIA resulted in q(2) (cv) values of 0.600 and 0.523, and r(2) values of 0.995 and 0.994, respectively, which indicates that both methods have significant predictive capability. Connolly surface analysis, which mainly focused on steric force fields, was performed to complement the results from CoMFA and CoMSIA. This novel study combining FPIA with pharmacophore modeling demonstrates that multidisciplinary research is useful for investigating antigen-antibody interactions and also may provide information required for the design of new haptens.  相似文献   
9.
10.
The quantitative structure-activity relationship (QSAR) of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives was studied. Three different alignment methods were used to get the models of the comparative molecular field analysis (CoMFA), the comparative molecular similarity indices analysis (CoMSIA), and the hologram quantitative structure-activity relationship (HQSAR). The statistical results from the established models show believable predictivity based on the cross-validated value (q 2>0.5) and the non-validated value (r 2>0.9). The analysis on contour maps of CoMFA and CoMSIA models suggests that hydrophobic and hydrogen-bond acceptor fields are important factors that affect the AT1 antagonistic activity of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives besides the steric and electrostatic fields. The structural modification information from different atom contributions in the HQSAR model is in agreement with that in the 3D-QSAR models.  相似文献   
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