两类HPPD酶抑制剂的比较分子场分析研究

用比较分子场分析法（CoMFA）研究了环已二酮类及3-烷基酸-2-环已烯酯类化 合物的结构与活性的关系。本研究从蛋白酶与底物动力学模拟的复合物结构出发构 建两类抑制剂化合物分子的构象，并进行了全空间搜索，CoMFA分析得到了较好的 模型（交叉验证回归系数q~2 = 0.779，模型的线性回归系数r~2 = 0.989）。该方 程不仅可以帮助推测抑制剂与受体的结合方式，还可定量地预测结构相近的类似物 活性，为设计合成新的HPPD酶抑制剂提供了理论依据。     

Comparative molecular field analysis and energy interaction studies of thrombin-inhibitor complexes

A Comparative Molecular Field Analysis (CoMFA) and an interaction energy-based method were applied on a database holding the 3D structures of 29 thrombin-inhibitor complexes. Several parameters were optimized in both methods in order to obtain the best correlation between theoretical and experimentally determined binding (Ki) data. CoMFA, which only uses the information of the inhibitors, performed best (r = 0.99, q2 = 0.46, N = 29) when HF 6-31G charges were used in combination with a pharmacophore-based alignment. Inclusion of hydrophobic fields did not lead to improvements. The interaction energy-based approach uses the information of the whole thrombin-inhibitor complex. A statistically significant correlation (r = 0.74, N = 14) could only be obtained for a subset of the database containing the high resolution structures. Geometry optimization of the ligand only in combination with downscaled electrostatics performed best.     

3D-QSAR Study on Diindolylmethane and Its Analogues with Comparative Molecular Field Analysis (CoMFA)

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Inhibitors of prolyl endopeptidase: Characterization of the pharmacophoric pattern using conformational analysis and 3D-QSAR

Summary A structure-activity study has been carried out on several compounds known as inhibitors of the serine protease prolyl endopeptidase. Conformational analysis has been done using different molecular mechanics methods such as molecular dynamics, or a randomized conformational search method. The conformers obtained were classified using geometric and energetic criteria. A pattern recognition analysis was done in order to divide conformers according to families. The resulting dominant families, for all compounds investigated, showed very similar geometric features. Based on the lowest energy conformers obtained after randomized conformational analysis, a 3D-QSAR model was established using the CoMFA approach. The validity of this model was verified by prediciting correctly the activity of other molecules not used in the construction of this model.     

Comparative molecular field analysis and molecular modeling studies of 20-(S)- camptothecin analogs as inhibitors of DNA topoisomerase I and anticancer/antitumor agents

Conformational studies and comparative molecular field analysis (CoMFA) were undertakenfor a series of camptothecin (CPT) analogs to correlate topoisomerase I inhibition with thesteric and electrostatic properties of 32 known compounds. The resulting CoMFA modelshave been used to make predictions on novel CPT derivatives. Using the newly derived MM3parameters, a molecular database of the 32 CPT analogs was created. Various point atomiccharges were generated and assigned to the MM3 minimized structures, which were used inpartial least-squares analyses. Overall, CoMFA models with the greatest predictive validitywere obtained when both the R- and S-isomers were included in the data set, andsemiempirical charges were calculated for MM3 minimized low-energy lactone structures. Across-validated R2 of 0.758 and a non-cross-validated R2 of 0.916 were obtained for MM3minimized structures with PM3 ESP charges for the 32 CPT analogs. The derived QSARequations were used to assign topoisomerase I inhibition values for compounds in this studyand compounds not included in the original data set. Prior to its appearance in the literature,an IC50 of 103 nM was predicted for the 10,11-oxazole derivative. This CoMFA predictedvalue compared favorably with the recently reported value of 150 nM. The CoMFA modelwas also evaluated by predicting the activities of recently reported 11-aza CPT and trionederivatives. The predicted activity (IC50 = 249 nM) for 11-aza CPT compared well with thereported value of 383 nM.     

Chiral recognition by enantioselective liquid chromatography: Mechanisms and modern chiral stationary phases

An overview of the state-of-the-art in LC enantiomer separation is presented. This tutorial review is mainly focused on mechanisms of chiral recognition and enantiomer distinction of popular chiral selectors and corresponding chiral stationary phases including discussions of thermodynamics, additivity principle of binding increments, site-selective thermodynamics, extrathermodynamic approaches, methods employed for the investigation of dominating intermolecular interactions and complex structures such as spectroscopic methods (IR, NMR), X-ray diffraction and computational methods. Modern chiral stationary phases are discussed with particular focus on those that are commercially available and broadly used. It is attempted to provide the reader with vivid images of molecular recognition mechanisms of selected chiral selector–selectand pairs on basis of solid-state X-ray crystal structures and simulated computer models, respectively. Such snapshot images illustrated in this communication unfortunately cannot account for the molecular dynamics of the real world, but are supposed to be helpful for the understanding. The exploding number of papers about applications of various chiral stationary phases in numerous fields of enantiomer separations is not covered systematically.     

3D-QSAR study,docking molecular and simulation dynamic on series of benzimidazole derivatives as anti-cancer agents

Benzimidazole is an important heterocyclic organic compound which has a structural analogy to nucleotides found in human body and hence is an important pharmacophore in medicinal chemistry. The anti-cancer activities for a diverse set of benzimidazole as anti-cancer agents against breast cancer cell line (MCF7) assay have been subjected to 3D-QSAR (3-Dimensional Quantitative Structural-Activity Relationship) studies. Both CoMFA and CoMSIA models exhibit significant results in terms of statistical parameters as determination coefficients R² > 0.9 and Leave One Out cross-validation determination coefficients Q²> 6. The predictive quality of both 3D QSAR models have been assessed by external validation and Y-randomization test. Five new compounds have been designed and predicted by in silico ADMET method. In the second part, we have used the docking molecular and simulation dynamics (MD) to investigate the bonding interactions and stability of the designed compounds into the Pin1. Then, we have compared them to Trastuzumab and Tamoxifen as a standard inhibitors drug of breast cancer. The designed compounds form stable hydrogen and hydrophobic bonding interactions with the residues Lys63, Gln131, Ser154, Arg 68 and Arg69 of Pin1 receptor during 100 ns as a time of the simulation. The obtained results showed that the new benzimidazole are useful as a template for future design of more potent inhibitors against breast cancer cell lines (MCF7).     

3D-QSAR Study on the Inhibitory Activity of Flavonoids on PIM-1 Kinase

20 Typical flavonoids were selected for study on the interaction between them and PIM-1 kinase with the comparative molecular field analysis method(CoMFA) as well as the comparative molecular similarity index analysis method(CoMSIA) based on molecule docking.3D-QSAR models between these flavonoids and receptor PIM-1 kinase were established.The obtained optimal cross-validation correlation coefficient Q2 for CoMFA model was 0.582,and the non-cross-validation correlation coefficient R2 was 0.955;the corresponding values for CoMSIA model were 0.790 and 0.974,respectively.These two models showed fairly fine stability and predictive ability.In addition,molecule docking results revealed the key residues in the receptor cavity and their specific action ways with flavonoids.     

3D-QSAR Study on a Series of Indolo[1,2-b]quinazoline Derivatives with Anticancer Activity and their Molecular Design

Indolo[1,2-b]quinazoline derivatives have recently been reported as a type of compound with potential anticancer activity. On the basis of our the published two-dimensional quantitative structure-activity relationship (2D-QSAR) of these compounds, a further study on the three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out using the method of comparative molecular field analysis (CoMFA). A reasonable, receivable, and an effective 3D-QSAR model has been established, in which the correlation coefficient (r²) and cross-validation coefficient (q²) values are 0.986 and 0.695, respectively, the statistical squared deviation ratio (F) is 114.6, and the standard deviation (SD) is 0.084. The results suggest that the electrostatic effect of substituent R₁ and steric effect of substituent R₂ play a very important role in the improvement of the anticancer activity of these compounds. In this article, some significant conclusions, which are in good agreement with the conclusions obtained using 2D-QSAR, were drawn as follows. (1) The electrostatic effect in the substituent R₁ part plays a major role, and it is very important to make the first atom of R₁ carrying more positive charges in order to improve the anticancer activity of the compounds. (2) The steric effect plays a major role in the substituent R₂ part, and the volume of R₂ should be moderate. Based on the above conclusions, three new molecules of Indolo[1,2-b]quinazoline derivatives with higher anticancer activity have been theoretically designed and are waiting for support from experiment. The QSAR results can offer a theoretical reference for the pharmaceutical synthesis.