Pharmacophore Identification and Validation Study of CK2 Inhibitors Using CoMFA/CoMSIA

Protein kinase CK2, also known as casein kinase‐2, has been found to be involved in cell growth, proliferation and suppression of apoptosis, which is related to human cancers. The series of compounds were identified as casein kinase‐2 inhibitors and their inhibitory activities are a function of a variation of their structures. The current study deals with the pharmacophore identification and, accordingly, the three‐dimensional quantitative structure–activity relationship model development using Pharmacophore Alignment and Scoring Engine. Several hypotheses were developed for the molecular alignments. On the basis of statistical values, the best‐fitted model was identified and the same alignment was used for 3D‐QSAR using comparative molecular field analysis/comparative molecular similarity index analysis. Both the CoMFA (R ²_CV = 0.58, R ² = 0.82 and r ²_pred = 0.62) and the comparative molecular similarity index analysis (R ²_CV = 0.74, R ² = 0.98 and r ²_pred = 0.81) gave reasonable results. Besides pharmacophore‐based alignment, the maximum common substructure‐based alignment was also used for the comparative molecular field analysis and comparative molecular similarity index analysis. The pharmacophore‐based alignment was more prominent and it has provided important information for the modelling of potent inhibitors. The overall study implies that a highly positive and bulky group with H‐bond donating property is desirable around the nitrogen atom adjacent to the pyrrolidine ring.     

2‐Pyridinyl‐4(3H)‐Quinazolinone: A Scaffold for Anti‐influenza A Virus Compounds

A series of 2‐pyridinyl‐3‐substituted‐4(3H)‐quinazolinones were synthesized, and their anti‐influenza A virus activities were determined using the cytopathic effect inhibition assay. Most of the compounds were potent with IC₅₀ values ranging from 51.6 to 93.0 μm , which are better than that of the currently marketed drug ribavirin. The molecular mechanisms of the new compounds were investigated using neuraminidase inhibition assay, cellular NF‐κB signaling pathway inhibition assay, and computational docking. Compound 4e , which is a N3 imidazol‐1‐ylpropyl‐substituted derivative of 2‐pyridinyl‐4(3H)‐quinazolinone, had the most potent anti‐influenza A virus activity in vitro, and inhibited both virus neuraminidase and cellular NF‐κB signaling pathway. In conclusion, 2‐pyridinyl‐4(3H)‐quinazolinone is a new scaffold for the design of potent anti‐influenza A virus compounds, offering an alternative approach to tackle influenza drug resistance.     

Quantitative structure–activity relationship studies of diarylpyrimidine derivatives as anti-HIV drugs using new three-dimensional structure descriptors

A novel three-dimensional holographic vector of atomic interaction field (3D-HoVAIF) was used to describe the chemical structures of 34 wild-type DAPYs, 33 mutant form L100I, 30 mutant form Y181C and 29 mutant form Y188L as anti-HIV drugs. Here four quantitative structure activity relationship models were built by partial least square regression. The estimation stability and prediction ability of models were strictly analyzed by both internal and external validations. The correlation coefficient (R _cum ² ), leave-one-out cross-validation correlation coefficient (Q _CV ² ) and predicted values versus experimental ones of external samples (Q _ext ² ) were 0.925, 0.769 and 0.949 for 34 diarylpyrimidines; 0.899, 0.788 and 0.889 for 33 mutant form L100I; 0.844, 0.761 and 0.935 for 30 mutant form Y181C; 0.890, 0.757 and 0.912 for 29 mutant form Y188L. These values indicated that the built PLS models had both favorable estimation stability and good prediction capabilities. Furthermore, the satisfactory results showed that 3D-HoVAIF could preferably express the information related to the biological activity of DAPY derivatives.     

Computational Study and Modified Design of Selective Dopamine D3 Receptor Agonists

Dopamine D₃ receptor (D₃R) is considered as a potential target for the treatment of nervous system disorders, such as Parkinson's disease. Current research interests primarily focus on the discovery and design of potent D₃ agonists. In this work, we selected 40 D₃R agonists as the research system. Comparative molecular field analysis (CoMFA) of three‐dimensional quantitative structure–activity relationship (3D‐QSAR), structure–selectivity relationship (3D‐QSSR), and molecular docking was performed on D₃ receptor agonists to obtain the details at atomic level. The results indicated that both the CoMFA model (r² = 0.982, q² = 0.503, = 0.893, SEE = 0.057, F = 166.308) for structure–activity and (r² = 0.876, q² = 0.436, = 0.828, F = 52.645) for structure–selectivity have good predictive capabilities. Furthermore, docking studies on three compounds binding to D₃ receptor were performed to analyze the binding modes and interactions. The results elucidate that agonists formed hydrogen bond and hydrophobic interactions with key residues. Finally, we designed six molecules under the guidance of 3D‐QSAR/QSSR models. The activity and selectivity of designed molecules have been improved, and ADMET properties demonstrate they have low probability of hepatotoxicity (<0.5). These results from 3D‐QSAR/QSSR and docking studies have great significance for designing novel dopamine D₃ selective agonists in the future.     

芦丁对流感病毒的体外抑制作用及其机制研究

目的研究芦丁对流感病毒的体外抑制作用并探讨其机制。方法利用流感病毒感染MDCK细胞模型,观察芦丁对流感病毒的体外抑制作用;结合流感病毒感染前、感染同时及感染后加药的不同方式探索芦丁作用于流感病毒生命周期的具体阶段;采用荧光底物法考察芦丁对流感病毒神经氨酸酶的抑制作用。结果芦丁对A/Puerto Rico/8/1934(H1N1)、A/FM1/1/47(H1N1)、A/Human/Hubei/3/2005(H3N2)、A/Beijing/32/92(H3N2)4株流感病毒均具有体外抑制作用,其中对A/Puerto Rico/8/1934(H1N1)株的半数有效浓度(EC50)最小,选择指数(SI)最大,体外药效最好。芦丁在流感病毒感染后给药的效果最为明显,对流感病毒A/FM1/1/47(H1N1)的IC50最小,对神经氨酸酶活性抑制作用相对最好。结论芦丁抑制了流感病毒神经氨酸酶活性,具有较好的体外抗流感病毒作用。     

The hydrophobic side chain of oseltamivir influences type A subtype selectivity of neuraminidase inhibitors

Neuraminidase, which plays a critical role in the influenza virus life cycle, is a target for new therapeutic agents. The study of structure–activity relationships revealed that the C‐5 position amino group of oseltamivir was pointed to 150‐cavity of the neuraminidase in group 1. This cavity is important for selectivity of inhibitors against N1 versus N2 NA. A serial of influenza neuraminidase inhibitors with the oseltamivir scaffold containing lipophilic side chains at the C‐5 position have been synthesized and evaluated for their influenza neuraminidase inhibitory activity and selectivity. The results indicated that compound 13o (H5N1 IC₅₀ = 0.1 ± 0.04 μm , H3N2 IC₅₀ = 0.26 ± 0.18 μm ) showed better inhibitory activity and selectivity against the group 1 neuraminidase. This study may provide a clue to design of better group 1 neuraminidase inhibitors.     

QSAR studies of antituberculosis drug using three-dimensional structure descriptors

A newly developed three-dimensional holographic vector of atomic interaction field (3D-HoVAIF) was used to describe the chemical structures of 28 arylamide derivatives as antituberculosis drug. Here, a quantitative structure activity relationship model was built by partial least square regression (PLS). The estimation stability and generalization ability of the model was strictly analyzed by both internal and external validations. The correlation coefficients of established PLS model (R ²), leave-one-out cross-validation (Q _LOO ² ), and predicted values versus experimental ones of external samples (Q _ext ² ) were 0.800, 0.778 and 0.821, respectively. The results of PLS exhibited both favorable estimation stability and good prediction capability. Thus, this newly developed 3D-HoVAIF could preferably express information related to biological activity of arylamide derivatives.     

Theoretical studies of QSAR and molecular design on a novel series of ethynyl-3-quinolinecarbonitriles as SRC inhibitors

A theoretical study on the two‐dimensional, three‐dimensional quantitative structure–activity relationships and docking analysis of a novel series of ethynyl‐3‐quinolinecarbonitriles acting as Src inhibitors has been carried out. To correlate the c‐Src kinase‐inhibition activity of these compounds with the two‐dimensional and three‐dimensional structural properties for 39 known compounds, some excellent quantitative structure–activity relationships models with satisfying internal and external predictive abilities were established. A combined method of the density functional theory, molecular mechanics and statistics as well as the comparative molecular field analysis was applied to develop two‐dimensional‐ and three‐dimensional‐quantitative structure–activity relationship models. The leave‐one‐out cross‐validation q² values of two‐dimensional‐quantitative structure–activity relationship and comparative molecular field analysis models are 0.834 and 0.812, respectively. The predictive abilities of these models were further validated by the test set including 10 compounds, and the predicted IC₅₀ values were in a good agreement with the experimental ones. The appropriate binding orientations and conformations of these compounds interacting with c‐Src kinase were also revealed by the docking study. Based on two‐dimensional‐ and three‐dimensional‐quantitative structure–activity relationship results along with docking analysis, some important factors responsible for inhibitory activity of this series of compounds were discussed in detail. These factors can be summarized as follows: selecting certain large‐size substituent R₂, increasing the negative charge of the first atom of substituent R₁ and the net charge of the C₁₅ atom on ring‐C will enhance the activity. Meanwhile, the interaction information between protein and ligand was also revealed in detail. These results help to understand the action mechanism and designing novel potential Src inhibitors. Based on the established models and some designing considerations, three new compounds with rather high predicted Src‐inhibitory activity have been theoretically designed and presented to experimenters for reference.     

Insight into the Structural Features of Pyrazolopyrimidine‐ and Pyrazolopyridine‐based B‐RafV600E Kinase Inhibitors by Computational Explorations

Presently, both ligand‐based and receptor‐based 3D‐QSAR modelings were performed on 107 pyrazolopyrimidine‐ and pyrazolopyridine‐based inhibitors of B‐Raf^V600E kinase. The optimal model is successful to predict the inhibitors' activity with Q² of 0.504, R²_ncv of 0.960, and R²_pred of 0.872. Besides, the 3D contour maps explain well the structural requirements of the interaction between the ligand and the receptor. Furthermore, molecular docking and MD were also carried out to study the binding mode. Our findings are the following: (i) Bulky substituents at position 3, 10 and ring D improve the inhibitory activity, but impair the activity at position 5, 11, and 19. (ii) Electropositive groups at position 10, 13 and 20 and electronegative groups at position 2 increase the biological activity. (iii) Hydrophobic substituents at ring C are beneficial to improve the biological activity, while hydrophilic substituents at position 11 and ring D are good for the activity. (4) This scaffold of inhibitors may bind to the B‐Raf kinase with an ‘L’ conformation and belong to type III binding mode, which is fixed by hydrophobic interaction and hydrogen bonds with residues from hinge region and DFG motif. These results may be a guidance to develop new B‐Raf^V600E kinase inhibitors.     

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.     

Characterization of the dopamine D3 receptor agonist R(+)‐7‐hydroxy‐N,N‐di‐n‐propyl‐2‐aminotetralin‐induced hypo‐ and hypermotility in mice

The present study was designed to characterize the dopamine D₃ receptor agonist R(+)‐7‐hydroxy‐N,N‐di‐n‐propyl‐2‐aminotetralin (R(+)‐7‐OH‐DPAT)‐induced changes in locomotor activity in mice. Although R(+)‐7‐OH‐DPAT (0·01–10 mg/kg) produced a significant decrease in horizontal and vertical motility within 15 min after the start of behavioural measurements, the dopamine D₁ receptor antagonist R(+)‐SCH23390 (0·05 mg/kg) and the dopamine D₃ receptor antagonist (+)‐UH232 (10 mg/kg) had no antagonistic effects on the R(+)‐7‐OH‐DPAT (3 mg/kg)‐induced hypomotility, while the dopamine D₂ receptor antagonist S(−)‐sulpiride (20 mg/kg) augmented it. Although R(+)‐7‐OH‐DPAT (0·01–1 mg/kg) had no marked effects on horizontal or vertical motility, higher doses (3 and 10 mg/kg) of the drug produced a significant increase in horizontal or vertical motility from 30 to 90 min after the start of the behavioural measurements. S(−)‐sulpiride (20 mg/kg) and (+)‐UH232 (10 mg/kg) almost completely inhibited the R(+)‐7‐OH‐DPAT (3 mg/kg)‐induced hypermotility, whereas the antagonistic effects of R(+)‐SCH23390 (0·05 mg/kg) were partial. These results suggest that the R(+)‐7‐OH‐DPAT‐induced hypermotility is mediated principally via dopamine D₂ and D₃ receptors, whereas it is unlikely that the hypomotility results from the activation of presynaptic dopamine D₂ or D₃ receptors. Copyright © 1999 John Wiley & Sons, Ltd.     

Combined 3D‐QSAR Modeling and Molecular Docking Study on Quinoline Derivatives as Inhibitors of P‐selectin

P‐selectin is a promising target for developing novel atherosclerosis drugs. To understand the structure–activity correlation of quinolines‐based P‐selectin inhibitors, we have carried out a combined molecular docking and three‐dimensional quantitative structure–activity relationship (3D‐QSAR) modeling study. The study has resulted in two types of satisfactory 3D‐QSAR models, including the CoMFA model (r², 0.863; q², 0.589) and CoMSIA model (r², 0.866; q², 0.636), to predict the biological activity of new compounds. The detailed microscopic structures of P‐selectin binding with inhibitors have been studied by molecular docking. We have also developed docking based 3D‐QSAR models (CoMFA with r², 0.934; q², 0.591; CoMSIA with r², 0.896; q², 0.573). The contour maps obtained from the 3D‐QSAR models in combination with the docked binding structures help to better interpret the structure–activity relationship. All of the structural insights obtained from both the 3D‐QSAR contour maps and molecular docking are consistent with the available experimental activity data. The satisfactory results strongly suggest that the developed 3D‐QSAR models and the obtained P‐selectin‐inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and in future drug design.     

The activity prediction of indole inhibitors against HCV NS5B polymerase

Non‐structural viral protein 5B (NS5B) is a viral protein in hepatitis C virus. Although various inhibitors against NS5B have been found, the activity prediction of similar untested inhibitors is still highly desirable. In this respect, the Tchebichef moments (TMs) calculated from the images of molecular structures were regarded as the independent variables while the inhibitory activity (pIC₅₀) was the dependent variable, and the predictive model was established by means of stepwise regression. The R‐squared of leave‐one‐out cross‐validation (Q²) for the training set and the R‐squared of prediction () for external independent test set were 0.919 and 0.927, respectively. The obtained model was also evaluated strictly. Compared with the multivariate curve resolution with alternating least squares (MCR‐ALS) and the QSAR approaches derived from the literature, the proposed method is more accurate and reliable. This study not only provides an effective approach to predict the biological activity of RNA replication's inhibitors, but also extends the QSAR modeling technique.     

A two‐step one‐pot radiosynthesis of the potent dopamine D2/D3 agonist PET radioligand [11C]MNPA

(R)‐(?)‐2‐[¹¹C]Methoxy‐N‐n‐propylnorapomorphine ([¹¹C]MNPA ([¹¹C]2)) is an agonist radioligand of interest for imaging D₂/D₃ receptors in vivo. Here we sought to develop an improved radiosynthesis of this radioligand. Reference 2 was synthesized in nine steps with an overall yield of about 5%, starting from codeine. Trimethylsilyldiazomethane proved to be a practical improvement in comparison to diazomethane in the penultimate methylation step. A protected precursor for radiolabeling ((R)‐(?)‐2‐hydroxy‐10,11‐acetonide‐N‐n‐propylnoraporphine, 4) was prepared from (R)‐(?)‐2‐hydroxy‐N‐n‐propylnorapomorphine (1) in 30% yield. [¹¹C]2 was prepared from 4 via a two‐step one‐pot radiosynthesis. The first step, methylation of 4 with [¹¹C]methyl triflate, occurred in quantitative radiochemical yield. The second step, deprotection of the catechol moiety with HCl and heat, yielded 60–90% of [¹¹C]2 giving an overall incorporation yield from [¹¹C]methyl triflate of 60–90%. In a typical run more than 1 GBq of [¹¹C]2, was produced from carbon‐11 generated from a 10‐min proton irradiation (16 MeV; 35 µA) of nitrogen–hydrogen target gas. The radiochemical purity of [¹¹C]2 was > 99% and specific radioactivity at the time of injection was 901±342 GBq/µmol (n=10). The total synthesis time was 35–38 min from the end of radionuclide production. The identity of [¹¹C]2 was confirmed by comparing its LC‐MS/MS spectrum with those of reference 2 and (R)‐(?)‐10‐methoxy‐2,11‐dihydroxy‐N‐n‐propylnoraporphine. Copyright © 2009 John Wiley & Sons, Ltd.