3-羧基香豆素类乳酸转运抑制剂的三维定量构效关系研究

目的 建立3-羧基香豆素类乳酸转运抑制剂三维定量构效关系(3D-QSAR)模型.方法 采用分子力场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)来研究3-羧基香豆素类乳酸转运抑制剂的构效关系.结果 建立了合理、可靠的3-羧基香豆素类乳酸转运抑制剂CoMFA(q2=0.630,r2 =0.994,rpred2=0.909)和CoMSIA(q2=0.676,r2=0.972,rpred2 =0.574)模型.结论 构建的3D-QSAR模型揭示了3-羧基香豆素类化合物的结构和生物活性间的关系,可为该类乳酸转运抑制剂的进一步优化设计提供科学依据.     

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of some benzimidazole derivatives with trichomonicidal activity

Trichomonosis is a common sexually transmitted infectious disease linked to reproductive health complications. Recently, the benzimidazole nucleus has emerged as a promising scaffold to develop new trichomonicidal agents. Despite the fact that large amounts of experimental data have been accumulated over the past eight years, no quantitative studies have yet been reported on this class of compounds. In our effort to develop new antiparasitic benzimidazole derivatives, we report in this paper CoMFA and CoMSIA studies with an initial set of 70 benzimidazole derivatives with trichomonicidal activity. Four CoMFA models and eight CoMSIA models were generated; ten of these models had values of r² > 0.6 and q² > 0.5. The best CoMFA model had r² = 0.936 and q² = 0.634, and the best CoMSIA model had r² = 0.858 and q² = 0.642. These models were generated by using two conformer selection methodologies (minimum energy conformations and 3D similarity), and three charge types (Mulliken, Gasteiger-Hükel and electrostatic potential atomic charges). The putative active tautomers of 1H-benzimidazole derivatives were selected using 3D-QSAR calculations. All models were validated via an external test set with 13 molecules. The best models satisfied additional validation criteria. The contour maps generated show the most important features that a benzimidazole derivative should have for trichomonicidal activity; they also, suggest that substituents at the 2- and 6-positions are important in the generation of derivatives with strong activity.     

Quantitative Structure Activity Relationship between Diazabicyclo[4.2.0]octanes Derivatives and Nicotinic Acetylcholine Receptor Agonists

Three dimensional quantitative structure activity relationship between diazabicyclo[4.2.0]octanes and nicotinic acetylcholine receptor (hα4β2 and hα3β4) agonists was studied using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). From 11 CoMFA and CoMSIA models, CoMSIA with steric and electrostatic fields gave the best predictive models (q²=0.926 and 0.945, r²_ncv=0.983 and 0.988). This study can be used to develop potent hα4β2 receptor agonists with low activity on hα3β4 subtype.     

In vitro Antiviral Effects and 3D QSAR Study of Resveratrol Derivatives as Potent Inhibitors of Influenza H1N1 Neuraminidase

The anti-influenza virus activities of 50 resveratrol (RV: 3, 5, 4′-trihydroxy-trans-stilbene) derivatives were evaluated using a neuraminidase (NA) activity assay. The results showed that 35 compounds exerted an inhibitory effect on the NA activity of the influenza virus strain A/PR/8/34 (H1N1) with 50% inhibitory concentration (IC₅₀) values ranging from 3.56 to 186.1 μm . Next, the 35 RV derivatives were used to develop 3D quantitative structure–activity relationship (3D QSAR) models for understanding the chemical–biological interactions governing their activities against NA. The comparative molecular field analysis (CoMFA r² = 0.973, q² = 0.620, q_test² = 0.661) and the comparative molecular similarity indices analysis (CoMSIA r² = 0.956, q² = 0.610, q_test² = 0.531) were applied. Afterward, molecular docking was performed to study the molecular interactions between the RV derivatives and NA. Finally, a cytopathic effect (CPE) reduction assay was used to evaluate the antiviral effects of the RV derivatives in vitro. Time-of-addition studies demonstrated that the RV derivatives might have a direct effect on viral particle infectivity. Our results indicate that the RV derivatives are potentially useful antiviral compounds for new drug design and development for influenza treatment.     

3D-QSAR with the aid of pharmacophore search and docking-based alignments for farnesyltransferase inhibitors

Farnesyltransferase is a potential drug target for treating various types of cancers. Three-dimensional quantitative structure–activity relationships (3D-QSAR) for a series of farnesyltransferase inhibitors were investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Pharmacophore search and molecular docking methods were used for construction of the molecular alignments. While the 3D-QSAR models were created for a training set of 33 compounds, their external predictivity was proven using a test set of 12 compounds. The results provided a comprehensive insight into the relationship between the structural features and the activities of farnesyltransferase inhibitors. This investigation will facilitate optimization of the design of new potential farnesyltransferase inhibitors.     

Study on the anticancer activity of coumarin derivatives by molecular modeling

Protein kinase 2 (CK2) is a potential target, and the coumarins were identified as the attractive CK2 inhibitors. In this study, two models (CoMFA and CoMSIA) were established, and their reliabilities were supported by statistical parameters. From the CoMFA and CoMSIA models, the hydrophobic and hydrogen bonds play very important roles in the interactions between inhibitors and CK2, which were confirmed sufficiently by molecular docking. Furthermore, the binding mode of the inhibitors at the active sites of CK2 was also investigated by docking study. The hydroxyl at the position R(5) is more important for coumarins inhibitors because it forms hydrogen bonds not only with Lys68 as hydrogen acceptor but also with H(2) O as hydrogen donor. In addition, hydroxyl can make electrostatic interactions with electropositive Lys68 residue. The large group at the R(6) position is not conducive to inhibitor dock into the groove of the binding site of CK2. When there is nitro group, the electrostatic interaction between ligand and receptor is enhanced significantly, and the nitro oxygen can form hydrogen bonds with the backbone NH of Lys68 and Asp175 simultaneously. The results obtained from molecular modeling techniques not only provide the models to predict the activity of inhibitors but also lead to a better understanding of the interactions between inhibitors and CK2, which will be very helpful for drug design.     

Interaction of benzopyranone derivatives and related compounds with human concentrative nucleoside transporters 1, 2 and 3 heterologously expressed in porcine PK15 nucleoside transporter deficient cells. Structure-activity relationships and determinants of transporter affinity and selectivity

Unlike the major equilibrative nucleoside transporters, there is a dearth of potent specific inhibitors of concentrative nucleoside transporters (CNTs). We investigated the interaction of benzopyranone derivatives and related compounds with human (h) CNTs in newly established PK15NTD transfectant cells stably expressing hCNT1 or hCNT2, and previously established PK15NTD/hCNT3 cells. Flavones exhibited the highest inhibitory activity against hCNT2 and hCNT3, whereas the most potent selective inhibitor of hCNT1 was a coumarin derivative. hCNT3 was the only transporter that exhibited moderate sensitivity to the chalcones tested. The most active compound was 6-hydroxy-7-methoxyflavone, which was hCNT3-specific with an IC₅₀ of 0.57 ± 0.20 μM, and over 40-fold more potent than the standard CNT inhibitor, phloridzin (IC₅₀ of 25 ± 3.5 μM). The SAR (Structure-Activity Relationship) shows that high potency against all three hCNTs is conferred by the presence of hydroxyl substituents at both the 7- and 8-positions of flavones and isoflavones. CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) 3D-QSAR (three-Dimensional Quantitative Structure-Activity Relationship) modeling indicated that electrostatic and hydrophobic properties were the most influential for interactions between the flavonoids and hCNT1, while electrostatic, hydrophobic and hydrogen bond donor properties were predominate for interactions with hCNT2 and hCNT3. The 3D-QSAR results also suggested possible commonalities in hydrogen bonding interactions of flavonoids and nucleosides, suggesting similarities between the hCNT-binding sites of the two classes of compounds. We report the most potent and selective non-nucleoside CNT inhibitors to date; which may serve as research tools and/or leads for further inhibitor development.     

A 3D-QSAR study of catechol-O-methyltransferase inhibitors using CoMFA and CoMSIA

应用CoMFA方法和CoMSIA方法研究儿茶酚转甲基酶抑制剂的三维定量构效关系@艾纯芝$Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences!457 Zhongshan Road, Dalian 116023, Liaoning,China