Huabei Zhang

Name: 张华北; Zhang, HuaBei

Organization: Beijing Normal University , China

Department: College of Chemistry

Title: Professor(PhD)

Chemicals
References

Synthesis, biological evaluation, and molecular dynamics (MD) simulation studies of three novel F-18 labeled and focal adhesion kinase (FAK) targeted 5-bromo pyrimidines as radiotracers for tumor

Co-reporter:Yu Fang, Dawei Wang, Xingyu Xu, Jianping Liu, Aiqin Wu, Xiang Li, Qianqian Xue, Huan Wang, Hang Wang, Huabei Zhang

European Journal of Medicinal Chemistry 2017 Volume 127(Volume 127) pp:

Publication Date(Web):15 February 2017

DOI:10.1016/j.ejmech.2017.01.015

•This was the first attempt to develop the FAK targeted tumor diagnostic imaging agents on the radiopharmaceutical level.•Coronal micro-PET/CT images of a mouse bearing S180 tumor confirmed that [18F]2 could be accumulated in tumor.•The results of the molecular dynamics simulations consists with the changing trends of the interaction between F-19 standards and the FAK.Focal adhesion kinase (FAK) is considered as an attractive target for oncology. A series of F-18 labeled 5-bromo-N2-(4-(2-fluoro-pegylated (FPEG))-3,5-dimethoxyphenyl)-N4-(4-methoxyphenyl)pyrimidine-2,4-diamine derivatives were prepared and evaluated as the FAK targeted radiotracers for the early diagnoses of tumor. For the study of the FAK targeted drug molecules, this was the first attempt to develop the tumor diagnostic imaging agents on the radiopharmaceutical level. They inhibited the activity of FAK with IC50 in the range of 91.4–425.7 nM, and among which the result of the [19F]2 was relatively good and had a modest IC50 of 91.4 nM. The [19F]2 was also profiled in vitro against some other kinds of cancer-related kinases (including two kinds of non-receptor tyrosine kinase: PYK2 and JAK2, and three kinds of receptor tyrosine kinase: IGF-1R, EGFR and PDGFRβ). It displayed 25.2 folds selectivity against PYK2, 35.1 folds selectivity against EGFR, and more than 100 folds selectivity against IGF-1R, JAK2 and PDGFRβ. For the biodistribution in S180 bearing mice, the corresponding [18F]2 were also relatively good, with modest tumor uptake of 5.47 ± 0.19 and 5.80 ± 0.06 %ID/g at 15 and 30 min post-injection, respectively. Furthermore, its tumor/muscle, tumor/bone and tumor/blood ratio at 15 min post-injection were 3.16, 2.53 and 4.52, respectively. And its tumor/muscle, tumor/bone and tumor/blood ratio at 30 min post-injection were 3.14, 2.76 and 4.43, respectively. In addition, coronal micro-PET/CT images of a mouse bearing S180 tumor clearly confirmed that [18F]2 could be accumulated in tumor, especially at 30 min post-injection. Besides, for the [18F]2, both the biodistribution data and the micro-PET/CT imaging study showed significantly reduced uptake of the radiotracer in the tumor tissue at 30 min post-injection in mice that received PF-562,271 (one of the reported best selective FAK inhibitor which was developed by Pfitzer Inc. and inhibited the activity of FAK with IC50 value of 1.5 nM) at 1 h before the injection of radiotracer. In combination with the above kinase profiling assay, it could be indicated that the uptake of [18F]2 in tumor of the mouse model was due to FAK expression, and that [18F]2 might be a kind of selectively FAK targeted tumor imaging agents. What's more, the results of the MD (molecular dynamics) simulations were in agreement with the changing trends of the interaction between the different F-19 standards and the FAK (expressed as the in vitro inhibitory abilities of enzymatic activities of FAK in this article), which was also in agreement with and had great effect on the changing trends of the uptake of the corresponding F-18 labeled tracers in tumor and some of theirs target/non-target ratios.Download high-res image (284KB)Download full-size image

Synthesis and evaluation of novel F-18-labeled pyrimidine derivatives: potential FAK inhibitors and PET imaging agents for cancer detection

Co-reporter:Dawei Wang;Yu Fang;Hang Wang;Xingyu Xu;Jianping Liu

RSC Advances (2011-Present) 2017 vol. 7(Issue 36) pp:22388-22399

Publication Date(Web):2017/04/19

DOI:10.1039/C6RA28851K

Based on computer-assisted drug design, a series of novel pyrimidine derivatives was successfully synthesized and characterized by 1H NMR, 13C HNMR, and MS spectra. All the new compounds were evaluated for their activity against focal adhesion kinase and showed low IC50 values in comparison with control drugs. In particular, for compound 8i, its IC50 value was 0.060 μM, suggesting its advantage as a focal adhesion kinase inhibitor. To evaluate the potentiality of these compounds as PET imaging agents in cancer detection, compounds 8a, 8c, 8h, and 8i were successively labeled with 18F. The four 18F-labeled pyrimidine derivatives showed appropriate log P values and high stability in physiological saline and mouse plasma. Noticeably, compound [18F]-8a with a 4-methoxyl group at the benzene ring exhibited good in vivo biodistribution data in mice bearing the S180 tumor, which promoted a further microPET imaging study of compound [18F]-8a. The microPET image of [18F-8a] administered into the S180 tumor-bearing mice acquired at 60 min post-injection illustrated that the uptake in S180 tumor was obvious. These results suggested that compound [18F]-8a might be a new probe for PET tumor imaging.

Synthesis and bio-evaluation of Tc-99m-labeled fatty acid derivatives for myocardial metabolism imaging

Co-reporter:Jianping Liu;Qianqian Xue;Huan Wang;Hang Wang;Dawei Wang;Yu Fang

Applied Organometallic Chemistry 2016 Volume 30( Issue 7) pp:596-604

Publication Date(Web):

DOI:10.1002/aoc.3476

¹¹C, ¹⁸F and ¹²³I fatty acids are used for myocardial imaging, and ^99mTc-labeled fatty acids are more desirable substitutes than other radiolabeled fatty acids. In the work reported, [^99mTc]-CpTT-10-oxo-FPA (1c), [^99mTc]-CpTT-12-oxo-FPA (2c), [^99mTc]-CpTT-14-oxo-FPA (3c) and [^99mTc]-CpTT-16-oxo-FPA (4c) were prepared with 60.76–70.92% of radiochemical yield and purity of more than 95%. These radiotracers (1c, 2c, 3c, 4c) were chemically stable when incubated in Sprague Dawley rat serum for 3 h at 37 °C. Tissue distribution studies in female mice indicated that 2c had high initial heart uptake (8.84%ID g⁻¹ at 1 min post-injection) and 4c had long retention in the heart (1.45%ID g⁻¹ at 30 min post-injection). Metabolite analysis showed 4c could be metabolized to 5c via β-oxidation with loss of two CH₂ in the myocardium, the radiometabolite being excreted via urine. However, low heart uptake suggested that 4c cannot be used as a diagnostic imaging agent. Copyright © 2016 John Wiley & Sons, Ltd.

Density functional theory study of the Eu(III) and Am(III) complexes with two 1,10-phenanthroline-type ligands

Co-reporter:Yanqiu Yang, Shiyuan Hu, Yu Fang, Hongyuan Wei, Sheng Hu, Dawei Wang, Liang Yang, Huabei Zhang, Shunzhong Luo

Polyhedron 2015 Volume 95() pp:86-90

Publication Date(Web):27 July 2015

DOI:10.1016/j.poly.2015.03.032

We investigated the extraction complexes of Eu(III) and Am(III) with two 1,10-phenanthroline-type ligands primarily using density functional theory (DFT). The geometrical optimizations of the structures of the [ML2NO3]2+ species, can achieve the same accuracy and obtain the same geometrical configuration at both the B3LYP/6-31G(d)/RECP and MP2/6-31G(d)/RECP levels of theory. At the B3LYP/6-311G(d,p)/RECP level of theory, solvation is unfavorable to the formation of the complexes. However, it is the solvation that make the separation between the [AmL2(NO3)]2+ complexes and the [EuL2(NO3)]2+ complexes. Additionally, the introduction of strong hydrophobic substituents into ligands improves their selectivity for actinide/lanthanide in acidic media.Complexes of Eu(III) and Am(III) with the two 1,10-phenanthroline-type ligands have been studied primarily with the density functional theory method. The solvation is unfavorable to the formation of the complexes. Additionally, the introduction of strong hydrophobic substituents into extractants improves their selectivity for actinide/lanthanide in acidic media.

Complexation behavior of Eu(III), Tb(III), Tm(III), and Am(III) with three 1,10-phenanthroline-type ligands: insights from density functional theory

Co-reporter:Yanqiu Yang;Yu Fang;Jun Liu;Shiyuan Hu;Sheng Hu

Journal of Molecular Modeling 2015 Volume 21( Issue 7) pp:

Publication Date(Web):2015 July

DOI:10.1007/s00894-015-2721-2

Extraction complexes of Eu(III), Tb(III), Tm(III), and Am(III) with three 1,10-phenanthroline-type ligands have been studied, primarily using density functional theory (DFT). The same accuracies and optimized structural geometries were obtained whether optimization of the [ML2(NO3)]2+ complexes was performed at the B3LYP/6-31G(d)/RECP or the MP2/6-31G(d)/RECP level of theory. Calculations carried out at the B3LYP/6-311G(d, p)/RECP level of theory indicated that solvation does not favor the formation of these complexes. Moreover, the ΔGg and ΔGsolv values for the reactions leading to the formation of [LnL2(NO3)]2+ complexes were seen to decrease with increasing atomic number of the lanthanide (from Eu to Tb to Tm). In addition, when a strongly hydrophobic benzo[e][1,2,4]triazine group was created in each ligand, ligand selectivity for actinides/lanthanides in acidic media improved. Even greater ligand selectivity for actinides/lanthanides in acidic media was obtained when a 5,6-diphenyl-1,2,4-triazine group was created in each ligand instead of a benzo[e][1,2,4]triazine group. Vibrational analysis and NMR spectroscopic analysis were also performed on all of the studied ligands and the metal complexes that included them. Further in-depth investigations should be undertaken in this field.

Synthesis and biological evaluation of fatty acids conjugates bearing cyclopentadienyl-donors incorporated [99mTc/Re(CO)3]+ for myocardical imaging

Co-reporter:Huahui Zeng, Huabei Zhang

European Journal of Medicinal Chemistry 2014 Volume 72() pp:10-17

Publication Date(Web):24 January 2014

DOI:10.1016/j.ejmech.2013.11.015

•Tc-99m-labeled fatty acid is very important for evaluation of myocardial metabolism.•1b was radiolabeled by double ligand transfer reaction between ferrocene and 99mTc.•1b and 3b with chain branching has high uptake and prolongs retention in myocardium.Four 99mTc-labeled fatty acid analogs, 1b, 2b, 3b, 4b were synthesized by a double ligand transfer reaction and theirs potential were investigated. The radiochemical yield of the radiotracers was from 11.7% to 30.3% (no decay corrected). Those compounds were found to be chemically stable when incubated in SD rat serum for 3 h at 37 °C. The biodistribution studies in mice showed that high radioactivity accumulated of Tc-99m complexes were observed, followed by moderate clearance from the heart. The maximum heart/blood ratio was 5.7 at 15 min postinjection of 1b. Metabolite analysis showed 1b was not metabolized by β-oxidation in the heart. These results suggest that 1b may be a promising radiotracer for evaluation of myocardial viability.We synthesized 4 99mTc-labeled fatty acid analogs, 1b, 2b, 3b, 4b, and investigated their potentials as radiotracer for evaluating fatty acid metabolism in myocardium. 1b shows a more excellent potential than the others.

Combined 3D-QSAR, Molecular Docking, Molecular Dynamics Simulation, and Binding Free Energy Calculation Studies on the 5-Hydroxy-2H-Pyridazin-3-One Derivatives as HCV NS5B Polymerase Inhibitors

Co-reporter:Haijing Yu;Yu Fang;Xia Lu;Yongjuan Liu

Chemical Biology & Drug Design 2014 Volume 83( Issue 1) pp:89-105

Publication Date(Web):

DOI:10.1111/cbdd.12203

The NS5B RNA-dependent RNA polymerase (RdRP) is a promising therapeutic target for developing novel anti-hepatitis C virus (HCV) drugs. In this work, a combined molecular modeling study was performed on a series of 193 5-hydroxy-2H-pyridazin-3-one derivatives as inhibitors of HCV NS5B Polymerase. The best 3D-QSAR models, including CoMFA and CoMSIA, are based on receptor (or docking). Furthermore, a 40-ns molecular dynamics (MD) simulation and binding free energy calculations using docked structures of NS5B with ten compounds, which have diverse structures and pIC₅₀ values, were employed to determine the detailed binding process and to compare the binding modes of the inhibitors with different activities. On one side, the stability and rationality of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM-PBSA method gave a good correlation with the experimental biological activity. On the other side, by analyzing some differences between the molecular docking and the MD simulation results, we can find that the MD simulation could also remedy the defects of molecular docking. The analyses of the combined molecular modeling results have identified that Tyr448, Ser556, and Asp318 are the key amino acid residues in the NS5B binding pocket. The results from this study can provide some insights into the development of novel potent NS5B inhibitors.

Receptor and ligand-based 3D-QSAR study on a series of pyrazines/pyrrolidylquinazolines as inhibitors of PDE10A enzyme

Co-reporter:Yongjuan Liu;Xia Lu;Tian Xue;Shiyuan Hu

Medicinal Chemistry Research 2014 Volume 23( Issue 2) pp:775-789

Publication Date(Web):2014 February

DOI:10.1007/s00044-013-0619-z

The 3D-QSAR analysis was performed on the set of 175 potent inhibitors of the PDE10A enzyme. Four separate models were built based on different conformations and superimposition methods. They were generated following next criteria: (I) database alignment based on the conformations most similar to the co-crystalized ligand conformation, (II) database alignment based on the minimum energy conformations, (III) docking alignment based on the docked conformations, and (IV) database alignment based on the docking conformations. The best CoMFA and CoMSIA models, derived from superimposition III, show leave-one-out cross-validated correlation coefficient (q2) values of 0.673 and 0.707 as well as the non-cross-validated correlation coefficient (r2) values of 0.936 and 0.924, respectively. In addition, the satisfactory results, based on the bootstrapping analysis and 10- and 50-fold cross-validation, further indicate the highly statistical significance of the models. The external predictive abilities of these models were evaluated using a prediction set of 35 compounds, producing the predicted correlation coefficients. Results were graphically interpreted in terms of field contribution maps. A DISCOtech pharmacophore model was also constructed to light important structural features that could be responsible for the low- or high-inhibition activity.

Synthesis, characterization and biodistribution of new fatty acids conjugates bearing N,N,N-donors incorporated [99mTc/Re(CO)3]+

Co-reporter:Huahui Zeng, Lingzhou Zhao, Shiyuan Hu, Yongjuan Liu, Haijing Yu, Na Chen and Huabei Zhang

Dalton Transactions 2013 vol. 42(Issue 8) pp:2894-2901

Publication Date(Web):10 Dec 2012

DOI:10.1039/C2DT32492J

[99mTc(CO)3]+-6-[N-(2-dipicolyl)amino]hexanoic acid (1a) and [99mTc(CO)3]+-11-[N-(2-dipicolyl)amino]undecanoic acid (1b) were prepared by incorporating [99mTc-(CO)3]+ into 6-[N-(2-dipicolyl)amino]hexanoic acid and 11-[N-(2-dipicolyl)amino]undecanoic acid, respectively. The overall radiochemical yield of 1a and 1b was from 79.7% to 91.3% and radiochemical purity after HPLC purification was more than 94%. The resulting complexes were found to be chemically stable when incubated in SD rat serum for 3 h at 37 °C. Tissue distribution studies in normal mice showed that high initial uptake of Tc-99m complexes were observed, followed by slow clearance from the heart. The maximum heart-to-blood ratio of 1a was 1.46 at 60 min, but 1b showed a poor heart-to-blood ratio. By estimating the tissue distribution and the computing result of the molar volume and the solvation free energy of Tc-99m chelating groups, a small-size and monocationic Tc-99m core is very important to enhance the myocardial accumulation and low liver uptake for the fatty acid tracers.

Insight into the binding model of new antagonists of kappa receptor using docking and molecular dynamics simulation

Co-reporter:Shiyuan Hu;Haijing Yu;Yongjuan Liu;Tian Xue

Journal of Molecular Modeling 2013 Volume 19( Issue 8) pp:3087-3094

Publication Date(Web):2013 August

DOI:10.1007/s00894-013-1839-3

PF-4455242 and its analogues represent a new series of kappa opioid selective antagonists that demonstrate high selectivity and potency. We investigated their binding mode to the κ-receptor via docking and molecular dynamics simulations. The ranking of the predicted binding free energies is consistent with experimental results. Detailed binding free energies between antagonists and individual protein residues were calculated, and key residues involved in binding were identified. Deviation of the active site residues was investigated, and the results show that Gln115, Leu135, Tyr139, Trp287 and Tyr313 deviate greatly from the reference structure. Information obtained from molecular modeling studies will aid in the design of potent kappa receptor antagonists.

3D-QSAR study of multi-target-directed AchE inhibitors based on autodocking

Co-reporter:Na Chen;Chunkai Liu;Lingzhou Zhao

Medicinal Chemistry Research 2012 Volume 21( Issue 2) pp:245-256

Publication Date(Web):2012 February

DOI:10.1007/s00044-010-9516-x

We do some research about multi-target-directed AChE inhibitors of Tacrine–Nimodipine dihydropyridine. 3D-QSAR models have been built using CoMFA and CoMSIA methods, based on compounds which are very selective and potent AChEIs and show an excellent neuroprotective profile and a moderate Ca2+ channel blockade effect. These studies indicated that the QSAR models were statistically significant and high predictable (receptor-based research CoMFA model, q2 = 0.686, r2 = 0.948; CoMSIA model, q2 = 0.756, r2 = 0.907 in all of the models no. of components = 6). Consequently, based on these results, our models would offer help to better comprehend the structure–activity relationships existent for this class of compounds and also facilitate the design of novel inhibitors with good chemical property.

3D-QSAR study of Chk1 kinase inhibitors based on docking

Co-reporter:Lingzhou Zhao;Yongjuan Liu;Shiyuan Hu

Journal of Molecular Modeling 2012 Volume 18( Issue 8) pp:3669-3694

Publication Date(Web):2012 August

DOI:10.1007/s00894-012-1363-x

Checkpoint kinase 1 (Chk1), a kind of a serine/threonine protein kinase, plays a significant role in DNA damage-induced checkpoints. Chk1 inhibitors have been demonstrated to abrogate the S and G2 checkpoints and disrupt the DNA repair process, which results in immature mitotic progression, mitotic catastrophe, and cell death. Normal cells remain at the G1 phase via p53 to repair their DNA damages, and are less influenced by the abrogation of S and G2 checkpoint. Therefore, selective inhibitors of Chk1 may be of great therapeutic value in cancer treatment. In this paper, in order to understand the structure-activity relationship of macro-cyclic urea Chk1 inhibitors, a study combined molecular docking and 3D-QSAR modeling was carried out, which resulted in two substructure-based 3D-QSAR models, including the CoMFA model (r2, 0.873; q2, 0.572) and CoMSIA model (r2, 0.897; q2, 0.599). The detailed microscopic structures of Chk1 binding with inhibitors were performed by molecular docking. Two docking based 3D-QSAR models were developed (CoMFA with r2, 0.887; q2, 0.501; CoMSIA with r2, 0.872; q2, 0.520). The contour maps obtained from the 3D-QSAR models in combination with the docked binding structures would be helpful to better understand the structure–activity relationship. All the conclusions drawn from both the 3D-QSAR contour maps and molecular docking were in accordance with the experimental activity dates. The results suggested that the developed models and the obtained CHk1 inhibitor binding structures might be reliable to predict the activity of new inhibitors and reasonable for the future drug design.

Molecular Modeling Studies on Benzimidazole Carboxamide Derivatives as PARP-1 Inhibitors Using 3D-QSAR and Docking

Co-reporter:Huahui Zeng;Fubin Jang;Lingzhou Zhao ;Jianyuan Zhang

Chemical Biology & Drug Design 2011 Volume 78( Issue 3) pp:333-352

Publication Date(Web):

DOI:10.1111/j.1747-0285.2011.01139.x

Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP-1 inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. To understand the structure–activity correlation of cyclic amine-containing benzimidazole carboxamide-based PARP-1 inhibitors, we have carried out a combined molecular docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling study. Two types of satisfactory substructure-based 3D-QSAR models were built, including the comparative molecular field analysis (CoMFA) model (r², 0.913; q², 0.743) and comparative molecular similarity indices analysis (CoMSIA) model (r², 0.869; q², 0.734), to predict the biologic activity of new compounds. Docking studies were performed to explore the binding mode between all of the inhibitors and the PARP-1 and produce the bioactive conformation of each compound in the whole data set. The docked conformer-based alignment strategy gave the best 3D-QSAR models, CoMFA model (r², 0.899; q², 0.712) and CoMSIA model (r², 0.889; q², 0.744), respectively. The structural insights obtained from both the 3D-QSAR contour maps and molecular docking help to better interpret the structure–activity relationship. The information obtained from molecular modeling studies helped us to predict the activity of new inhibitors and further design some novel and potent PARP-1 enzyme inhibitors.

Preparation of classical Re/99mTc(CO)3+ and novel 99mTc(CO)2(NO)2+ cores complexed with flavonol derivatives and their binding characteristics for Aβ(1–40) aggregates

Co-reporter:Yang Yang, Lin Zhu, Mengchao Cui, Ruikun Tang, Huabei Zhang

Bioorganic & Medicinal Chemistry Letters 2010 Volume 20(Issue 17) pp:5337-5344

Publication Date(Web):1 September 2010

DOI:10.1016/j.bmcl.2010.04.026

Classical 99mTc(CO)3+ and novel 99mTc(CO)2(NO)2+ cores complexed with flavonol derivatives were prepared. Autoradiography of postmortem AD transgenic mice (Tg C57, APP, PS1 12-month-old) brain section confirmed the binding property of [99mTc(CO)3+-3-OH-flavone]0 to Aβ(1–40) aggregates, while the novel 99mTc(CO)2(NO)2+ labeled compounds showed no binding sites in AD transgenic mice sections. Intravenous administration of [99mTc(CO)3+-3-OH-flavone]0 resulted in moderate brain uptake (0.48 ± 0.05%ID/g) at 5 min post-injection and slow clearance from the brain issues in 2 h post-injection (120 min: 0.39 ± 0.08%ID/g). Then an Aβ(1–40)-receptor-targeted Re(CO)3+-3-OH-flavone, was prepared to identify the structure of the technetium complex. UV–vis absorption and fluorescence emission properties have been studied at room temperature in order to determine the natures of the lowest electronically excited states of Re(CO)3+-3-OH-flavone and the ligand. The fluorescent rhenium complex Re(CO)3+-3-OH-flavone showed high affinity for Aβ(1–40) aggregates in vitro by fluorescence spectra (dissociation constant (Kd) = 11.16 nM). In conclusion, the results suggested that 99mTc(CO)3+-3-OH-flavone should be a suitable candidate as Aβ plaque SPECT imaging agent for AD.

Binding research on flavones as ligands of β-amyloid aggregates by fluorescence and their 3D-QSAR, docking studies

Co-reporter:Yang Yang, Lin Zhu, Xiangji Chen, Huabei Zhang

Journal of Molecular Graphics and Modelling 2010 Volume 29(Issue 4) pp:538-545

Publication Date(Web):December 2010

DOI:10.1016/j.jmgm.2010.10.006

The Kds (dissociation constants) of 21 flavone derivatives have been obtained by fluorescence in vitro when binding with Aβ(1–40) (β-amyloid(1–40)) aggregates protein. Extensive 3D-QSAR (quantitative structure–activity relationship) studies were performed on the fluorescent flavones, which are excellent ligands of Aβ(1–40) aggregates protein. Comparative molecular similarity indices analysis (CoMSIA) technique was used to relate the binding affinities with the ligand structures, and the QSAR model was obtained using the CoMFA technique. The QSAR model was proved to statistically significant and have high predictive power: the CoMSIA model yielded the cross-validated q2 = 0.512 and the non-cross-validated r2 = 0.911. This model showed that electrostatic (22.5%) and H-bond interaction (acceptor 15.3%; donor 45.1%) properties played major roles in ligand binding process. The QSAR model was further graphically interpreted in terms of field contribution maps. In order to further investigate the specific binding site of the flavones in the Aβ(1–40) aggregates, preliminary docking studies were performed. According to the 3D-QSAR results, the possible binding site in the protein was proposed in order to direct the molecular docking studies. A good correlation (R2: 0.846) between the calculated binding energies and the experimental binding affinities (pKds) suggests that the identified binding site is reliable. The 3D-QSAR model and the information of the ligand–protein interaction will be helpful in the selection of flavones to be structurally modified and labeled by a radio nuclide for imaging Aβ(1–40) aggregates in the AD (Alzheimer's disease) brain.Graphical abstractResearch highlights▶ Binding affinities of flavones with β-amyloid aggregates were obtained by fluorescence. ▶ The CoMSIA model and the information of the ligand–protein interaction will be helpful in the selection of flavones to be structurally modified and labeled by a radio nuclide for imaging Aβ(1–40) aggregates in the AD brain.

Combined 3D-QSAR modeling and molecular docking study on 1,4-dihydroindeno[1,2-c]pyrazoles as VEGFR-2 kinase inhibitors

Co-reporter:Huahui Zeng, Huabei Zhang

Journal of Molecular Graphics and Modelling 2010 Volume 29(Issue 1) pp:54-71

Publication Date(Web):24 August 2010

DOI:10.1016/j.jmgm.2010.04.004

The vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases VEGFR-2 are attractive targets for the development of novel anticancer agents. To understand the structure–activity correlation of 1,4-dihydroindeno[1,2-c]pyrazole-based VEGFR-2 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 substructure-based 3D-QSAR models, including the CoMFA model (r2, 0.931; q2, 0.600) and CoMSIA model (r2, 0.928; q2, 0.569), for predicting the biological activity of new compounds. The detailed microscopic structures of VEGFR-2 binding with inhibitors have been studied by molecular docking. We have also developed docking based 3D-QSAR models (CoMFA with r2, 0.958; q2, 0.563; CoMSIA with r2, 0.965; q2, 0.567). 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 VEGFR-2 inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and in future drug design.

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

Co-reporter:Huahui Zeng;Ran Cao

Chemical Biology & Drug Design 2009 Volume 74( Issue 6) pp:596-610

Publication Date(Web):

DOI:10.1111/j.1747-0285.2009.00893.x

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.

3D QSAR studies on a series of potent and high selective inhibitors for three kinases of RTK family

Co-reporter:Hongyu Cao, Huabei Zhang, Xuefang Zheng, Dabin Gao

Journal of Molecular Graphics and Modelling 2007 Volume 26(Issue 1) pp:236-245

Publication Date(Web):July 2007

DOI:10.1016/j.jmgm.2006.12.001

For targets belonging to the same family of receptors, inhibitors often act at more than one biological target and produce a synergistic effect. Separate CoMFA and CoMSIA models were developed from our data set for the KDR, cKit and Tie-2 inhibitors. These models showed excellent internal predictability and consistency, and validation using test-set compounds yielded a good predictive power for the pIC50 value. The field contour maps (CoMFA and CoMSIA) corresponding to the KDR, cKit and Tie-2 kinase subtypes reflected the characteristic similarities and differences between these types. These maps provided valuable information to facilitate structural modifications of the inhibitor to increase selectivity for the KDR over cKit and Tie-2.

QSAR study of a large set of 3-pyridyl ethers as ligands of the α4β2 nicotinic acetylcholine receptor

Co-reporter:Huabei Zhang, Hua Li, Qinqin Ma

Journal of Molecular Graphics and Modelling 2007 Volume 26(Issue 1) pp:226-235

Publication Date(Web):July 2007

DOI:10.1016/j.jmgm.2006.11.005

Extensive 3D-QSAR studies were performed on 158 diverse analogues of 3-pyridyl ethers, which are excellent ligands of α4β2 neuronal nicotinic acetylcholine receptor (NnAChR). Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques were used to relate the binding affinities with the ligand structures. Two QSAR models were obtained using CoMFA and CoMSIA techniques. The two QSAR models were proved to be statistically significant and have high predictive power. The best CoMFA model yielded the cross-validated q2 = 0.605 and the non-cross-validated r2 = 0.862. The derived model indicated the importance of steric (85.9%) as well as electrostatic (14.1%) contributions. The CoMFA model demonstrated the steric field as the major descriptor of the ligand binding. The best CoMSIA model gave q2 = 0.723 and r2 = 0.685. This model showed that steric (30.3%) and H-bond interaction (61.8%) properties played major roles in ligand binding process. The squares of correlation coefficient for external test set of 28 molecules were 0.723 and 0.685 for the CoMFA model and the CoMSIA model, respectively. The two models were further graphically interpreted in terms of field contribution maps. SAR studies were also performed on different series of compounds in order to get a more reasonable understanding of the interactions between the ligands and the receptor. With the results, we have also presumed some assistant elements as supplements to the traditional pharmacophoric elements. A crude vision of ligand localization in the ligand-binding pocket of the receptor was also obtained, which would favor for the docking study of this kind of ligands.

A new nonlinear equation for the tissue/blood partition coefficients of neutral compounds

Co-reporter:Huabei Zhang

Journal of Pharmaceutical Sciences 2004 Volume 93(Issue 6) pp:1595-1604

Publication Date(Web):7 APR 2004

DOI:10.1002/jps.20084

A nonlinear model equation based on tissue composition (a content of lipids, proteins, and water) for the tissue/blood partition coefficients of compounds was developed. Based on this model, our nonlinear regression analysis for neutral compounds partitioning into the kidney, brain, muscle, lung, liver, heart, and fat resulted in equations with high fitting power (training set: n = 166, r² = 0.851, s = 0.260, Q² = 0.833) and strong predictive power (test set: n = 49, r² = 0.851, s = 0.246, Q² = 0.836). This model shows that the tissue/blood partition coefficients of a compound depend strongly on tissue compositions. The magnitudes of partition coefficients of a compound in different tissues are mainly modulated by volume fractions or weight fractions of tissue compositions. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1595–1604, 2004