新型四氢萘类抗真菌化合物的三维定量构效关系研究

采用比较分子力场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA),系统研究了49个新型四氢萘类化合物抗真菌活性的三维定量构效关系。在CoMFA研究中,考察了网格点步长对统计结果的影响。在CoMSIA研究中,研究了各种分子场组合、网格点步长和衰减因子对模型统计结果的影响,发现立体场、静电场、疏水场和氢键受体场的组合可得到最佳模型。所建立的CoMFA和CoMSIA模型的交叉相关系数q~2值分别为0.618和0.613,均具有较强的预测能力。利用CoMFA和CoMSIA模型的三维等值线图直观地解释了化合物的构效关系,阐明了化合物结构中苯环和氨基上各位置取代基对抗真菌活性的影响,为进一步结构优化提供了重要依据。     

维甲类化合物构效关系研究:抗致癌活性的三维构效关系

使用比较分子场分析法(comparativemolecularfieldanalysis,CoMFA)[1]建立了一个维甲类化合物抗致癌活性的三维构效关系(3D-QSAR)模型,用交叉验证法(cros-validation)、和非交叉验证方法(non-cros-validation)分别验证和建立的分子场模型,高的交叉验证回归系数(R2CV=0.905)说明系列化合物分子周围空间场和静电场分布的差异与其生物活性差异间存在良好的相关性。用这个模型预测在建立模型时没有包括进去的三个化合物的活性,预测值接近实验值,提示该模型有较好的活性预测能力,可用来指导设计新的高活性维甲分子。化合物分子的最低能量构象未必是其活性构象。用得到的化合物最低能量构象进行CoMFA研究,其交叉验证系数较低(R²_CV=0.420),不具有统计学意义。但将部分分子的单键微弱旋转,构象能变化控制在2kcal·mol^-1之内,其它分子采取最低能量构象,则得到高的交叉验证系数。叠合的配体分子场模拟了配体分子周围的作用环境,反映受体结合部位与配体之间存在相互作用的基团和(或)原子的空间和静电性质,分子场模型在作为预测活性模板的同时也在一定程度上映射出受体结合部位的三维拓扑形状和理化特性。     

2-苯氧茚酮类乙酰胆碱酯酶抑制剂的3D-QSAR研究

目的研究2-苯氧茚酮类乙酰胆碱酯酶抑制剂的三维定量构效关系。方法采用比较分子力场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)对结构与活性的关系进行研究。结果CoMFA模型表明立体场和静电场对活性的贡献分别为0.805和0.195;CoMSIA模型阐明疏水场和氢键场对活性也有一定的影响。结论两种3D-QSAR模型都显示出相当高的预测能力,CoMFA和CoMSIA的交叉验证值q2分别为0.881和0.918,通过对两种3D-QSAR模型等势图的分析,可为开展进一步的药物设计和结构优化提供理论指导和依据。     

Combined comparative molecular field analysis,comparative molecular similarity indices analysis,molecular docking and molecular dynamics studies of histone deacetylase 6 inhibitors

Human histone deacetylase isoform 6 (HDAC6) has been shown to have an immense role in cell motility and aggresome formation and is being an attractive selective target for the treatment of multiple tumour types and neurodegenerative conditions. The discovery of selective HDAC6 inhibitors with new chemical functionalities is therefore of utmost interest to researchers. In order to examine the structural requirements for HDAC6‐specific inhibitors and to derive predictive model which can be used for designing new selective HDAC6 inhibitors, a three‐dimensional quantitative structure–activity relationship study was carried out on a diverse set of ligands using common feature‐based pharmacophore alignment followed by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The models displayed high correlation of 0.978 and 0.991 for best CoMFA and CoMSIA models, respectively, and a good statistical significance. The model could be used for predicting activities of the test set compounds as well as for deriving useful information regarding steric, electrostatic, hydrophobic properties of the molecules used in this study. Further, the training and test set molecules were docked into the HDAC6 binding site and molecular dynamics was carried out to suggest structural requirements for design of new inhibitors.     

CoMFA study of piperidine analogues of cocaine at the dopamine transporter: exploring the binding mode of the 3 alpha-substituent of the piperidine ring using pharmacophore-based flexible alignment

A 3D-QSAR CoMFA study of piperidine-based analogues of cocaine with flexible 3 alpha-substituents is described. A series of pharmacophore models were generated based on three representative compounds 1p, 2i, and 3c using the Genetic Algorithm Similarity Program (GASP) method. The flexible superposition of all studied compounds was performed for each pharmacophore model using the FlexS algorithm and the three-dimensional structure of 2i as a template. All sets of the overlaid structures with the top-ranked conformers were used for CoMFA modeling. Two best initial CoMFA models were selected and further optimized by identifying the best-fitting conformer of each compound. Compared with the initial models, the conventional correlation coefficients r(2) for the optimized models 1 and 2 were improved from 0.90 and 0.837 to 0.997 and 0.993, respectively. The leave-one-out cross-validated coefficients q(2) for the optimized models 1 and 2 were improved from 0.515 and 0.296 to 0.828 and 0.849, respectively. The results of the two CoMFA models suggest that both steric and electrostatic interactions play important roles in the binding of the 3 alpha-substituents of the piperidine-based analogues of cocaine. The contributions from steric and electrostatic fields for model 1 were 0.621 and 0.379, respectively. The contributions from steric and electrostatic fields for model 2 were 0.493 and 0.507, respectively. The two highly predictive CoMFA models indicate that the 3 alpha-substituent has two possible binding modes at the DAT. The CoMFA contour maps provide a visual representation of prospective binding modes of the 3 alpha-substituent of the piperidine-based analogues of cocaine and can be used to design novel DAT inhibitors that may be useful for the treatment of cocaine abuse and certain neurological disorders.     

Rational procedure for 3D-QSAR analysis using TRNOE experiments and computational methods: application to thermolysin inhibitors

The success or failure of 3D QSAR, particularly CoMFA, is most strongly dependent, especially for flexible compounds, on the conformation of the molecule used in the analysis, and on the orientation of the molecule relative to the other molecules in 3D space (i.e., alignment). The present study suggests a rational procedure for the estimation of binding conformation that uses the transferred nuclear Overhauser effect (TRNOE) experiment in combination with conformational analysis using CAMDAS (Conformational Analyzer with Molecular Dynamics And Sampling) program that is developed in our laboratory. In the next step the TRNOE-obtained conformation can be used as a reference template in order to obtain alignment of other ligands, that have a common binding site. In this step we used the SUPERPOSE program created in our laboratory, in order to estimate the binding conformation of other compounds, and to simultaneously obtain the alignment of compounds for CoMFA. The resulting CoMFA models could be expected to closely reproduce the interaction mode with protein represented by the reported X-ray results. In order to confirm the validity of our procedure described above, we show its application in obtaining CoMFA models of thermolysin inhibitors. We obtained twenty CoMFA models, and that with the highest q2 value (q2 = 0.701) was found to provide an interaction mode very similar to that represented by the X-ray results.     

用比较分子力场分析法研究青蒿素醚类和酯类衍生物的三维定量结构—活性关系(英文)

运用三维定量结构—活性关系分析方法—比较分子力场分析法(CoMFA),研究了青蒿素醚类和酯类衍生物的理化性质与抗疟活性的关系。选用的四种分子重叠模型,其计算结果均有较强的预测能力,其中模型B得到的分子立体场分布与Avery等的实验结果一致;模型A、B和C的静电场分布计算结果与我们的量子化学计算结果一致;模型D的预测结果表明,—C_6-O_2-O_1-C_(10)-O_3-C_7-O_4-C_(12)-O_5-和C_(16)是抗疟活性的重要基团。     

蛋白酪氨酸磷酸酶1B抑制剂的分子对接及三维定量构效关系研究

目的对文献报道的一系列芳环取代噻唑类蛋白酪氨酸磷酸酶1B(PTP1B)抑制剂进行分子对接及三维定量构效关系(3D-QSAR)研究。方法应用Surflex-Dock进行分子对接结合模式研究,并用比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)方法进行三维定量构效关系研究,建立具有良好预测能力的3D-QSAR模型。结果对接结果表明,该类结构可以很好地占据PTP1B的3个关键结合位点,大大提高了抑制剂与酶的亲和力。所建立的CoMFA模型交叉验证系数q~2为0.644,CoMSIA模型交叉验证系数q~2为0.719。结论获得的CoMFA和CoMSIA模型具有可靠的预测能力,可应用于指导该类化合物的设计。     

磷脂酶A2抑制剂的三维构效关系研究

对近两年来专利报道中三个系列24个磷脂酶A2抑制剂进行了三维构效关系的研究,采用分子场比较分析方法(CoMFA)寻找结构与活性之间的关系,建立了一个可靠的构效关系模型,为活性分子的进一步修饰和改造提供了信息。     

Molecular docking and 3D-QSAR studies of 2-substituted 1-indanone derivatives as acetylcholinesterase inhibitors

Aim： To explore the binding mode of 2-substituted 1-indanone derivatives with acetylcholinesterase （ACHE） and provide hints for the future design of new de- rivatives with higher potency and specificity. Methods： The GOLD-docking con- formations of the compounds in the active site of the enzyme were used in subse- quent studies. The highly reliable and predictive three-dimensional quantitative structure-activity relationship （3D-QSAR） models were achieved by comparative molecular field analysis （CoMFA） and comparative molecular similarity analysis （CoMSIA） methods. The predictive capabilities of the models were validated by an external test set. Moreover, the stabilities of the 3D-QSAR models were veri- fied by the leave-4-out cross-validation method. Results： The CoMFA and CoMSIA models were constructed successfully with a good cross-validated coef- ficient （q2） and a non-cross-validated coefficient （r2）. The q2 and r2 obtained from the leave- 1-out cross validation method were 0.784 and 0.974 in the CoMFA model and 0.736 and 0.947 in the CoMSIA model, respectively. The coefficient isocontour maps obtained from these models were compatible with the geometrical and physi- cochemical properties of ACHE. Conclusion： The contour map demonstrated that the binding affinity could be enhanced when the small protonated nitrogen moi- ety was replaced by a more hydrophobic and bulky group with a highly partial positive charge. The present study provides a better understanding of the inter- action between the inhibitors and ACHE, which is helpful for the discovery of new compounds with more potency and selective activity.     

3D-QSAR study of pyrrolidine derivatives as matrix metalloproteinase-2 inhibitors

In order to develop potent inhibitors of matrix metalloproteinase-2(MMP-2) as anticancer agents, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was established by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. This study correlates the MMP-2 inhibitory activities of 67 pyrrolidine derivatives to steric, electrostatic, hydrophobic, and hydrogen-bond donor and acceptor fields. After using two different molecular alignments, both CoMFA and CoMSIA models resulted in good statistical predictions, a case in point being their high q ² values of between 0.757 and 0.843. The CoMFA and CoMSIA models established herein will be helpful in understanding the structure–activity relationship of pyrrolidine derivatives as well as in the design of novel derivatives with enhanced MMP-2 inhibitory activity.     

3D-QSAR study of 20 （S）-camptothecin analogs

AIM: To build up a quantitative structure-activity relationship (QSAR) model of 20 (S)-camptothecin (CPT) analogs for the prediction of the activity of new CPT analogs for drug design. METHODS: A training set of 43 structurally diverse CPT analogs which were inhibitors of topoisomerase I were used to construct a quantitative structure-activity relationship model with a comparative molecular field analysis (CoMFA). The QSAR model was optimized using partial least squares (PLS) analysis. A test set of 10 compounds was evaluated using the model. RESULTS: The CoMFA model was constructed successfully, and a good cross-validated correlation was obtained in which q(2) was 0.495. Then, the analysis of the non-cross-validated PLS model in which r(2) was 0.935 was built and permitted demonstrations of high predictability for the activities of the 10 CPT analogs in the test set selected in random. CONCLUSION: The CoMFA model indicated that bulky negative-charged group at position 9, 10 and 11 of CPT would increase activity, but excessively increasing bulky group at position 10 is adverse to inhibitory activity; substituents that occupy position 7 with the bulky positive group will enhance the inhibitive activity. The model can be used to design new CPT analogs and understand the mechanism of action.     

Comparative molecular field analysis of quinoline derivatives as selective and noncompetitive mGluR1 antagonists

A 3D- QSAR model os Comparative Molecular Field Analysib (CoMFA) of 45 quinoline derivatives as metaborropic glutamate receptor subtype 1 (mGluR1) inhibitors wew investigated. The CoMFA analysis provided a model with q(2) value of 0.827 and r(2) value of 0.990, in which q(2) value of 0.827 and an r(2) value of 0.990, in which the good correlation between the inhibitory activities and the steric and electrostatic molecular field around the analoques was observed. The predictive ability of the models was validated using the set of 12 compounds that were not included in the training set of 33 compounds. These results provided further understanding of the relationship between the structural features of quinolone derivatives and its activities, which should be applicable to design and find new potential mGluR1 inhibitors.     

Antitumor agents. 199. Three-dimensional quantitative structure-activity relationship study of the colchicine binding site ligands using comparative molecular field analysis

Inhibitors of tubulin polymerization interacting at the colchicine binding site are potential anticancer agents. We have been involved in the synthesis of a number of colchicine site agents, such as thiocolchicinoids and allocolchicinoids, which are colchicine analogues, and 2-phenyl-quinolones and 2-aryl-naphthyridinones, which are the amino analogues of cytotoxic antimitotic flavonoids. The most cytotoxic of the latter compounds strongly inhibit binding of radiolabeled colchicine to tubulin, and these agents therefore probably bind in the colchicine site of tubulin. We have applied conventional CoMFA and q(2)-GRS CoMFA to identify the essential structural requirements for increasing the ability of these compounds to form tubulin complexes. The CoMFA model for the training set of 51 compounds yielded cross-validated R(2) (q(2)) values of 0.637 for conventional CoMFA and 0.692 for q(2)-GRS CoMFA. The predictive power of this model was confirmed by successful activity prediction for a test set of 53 compounds with known potencies as inhibitors of tubulin polymerization. The activities of 88% of the compounds were predicted with absolute value of residuals of less than 0.5. The predictive q(2) values were 0.546 for conventional CoMFA and 0.426 for q(2)-GRS CoMFA. The conventional CoMFA model with the highest predictive q(2) (0.546) was analyzed in detail in terms of underlying structure-activity relationships.     

Three-dimensional quantitative structure-activity relationships of cyclo-oxygenase-2 (COX-2) inhibitors: a comparative molecular field analysis

The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to an extensive series of 305 varied diarylheterocyclic derivatives known as COX-2 selective inhibitors. X-ray crystal structure of COX-2 bound with SC-558, a selective COX-2 inhibitor, was used to derive the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (229 compounds) and subsequently validated with the corresponding test sets (76 compounds). The best predictive model (n = 229, q(2) = 0.714, N = 8, r(2) = 0.905, s = 0.291, F = 261.545) was selected for further comparison of the CoMFA contour maps obtained for steric, electrostatic, and lipophilic fields with the enzyme structure. The high level of compatibility with the COX-2 enzyme topology shows the great accuracy of this model that can predict inhibitory activities for a wide range of compounds and offers important structural insight into designing novel antiinflammatory drugs prior to their synthesis.     

CoMFA study of novel phenyl ring-substituted 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter.

A series of phenyl ring-substituted analogues of 3alpha-(diphenylmethoxy)tropane (benztropine) has been prepared as novel probes for the dopamine transporter. Cross-validated comparative molecular field analysis (CoMFA) models of the binding domain on the dopamine transporter were constructed using 37 geometry-optimized structures of these compounds and their corresponding binding affinities (K(i) values) for the displacement of [(3)H]WIN 35,428 or potency of [(3)H]dopamine uptake inhibition (IC(50) values) in rat caudate putamen tissue. The most predictive model (q(2) = 0.78) correlated the steric component of CoMFA to the dependent variable of [(3)H]WIN 35,428 binding affinities. A novel series of seven phenyl ring-substituted analogues of 3alpha-(diphenylmethoxy)tropane was prepared, and our best molecular model was used to accurately predict their binding affinities. This study is the first to provide a CoMFA model for this class of dopamine uptake inhibitors. This model represents an advancement in the design of novel dopamine transporter ligands, based on 3alpha-(diphenylmethoxy)tropane, and further substantiates structure-activity relationships that have previously been proposed for this class of compounds. This CoMFA model can now be used to predict the binding affinities of novel 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter and will be useful in the design of molecular probes within this class of dopamine uptake inhibitors.