付伟
基于结构的抑制剂设计和发现,分子力学和分子动力学模拟及分子对接研究受体和药物小分子的相互作用,计算机辅助药物设计等。
个性化签名
- 姓名:付伟
- 目前身份:
- 担任导师情况:
- 学位:
-
学术头衔:
- 职称:-
-
学科领域:
药物化学
- 研究兴趣:基于结构的抑制剂设计和发现,分子力学和分子动力学模拟及分子对接研究受体和药物小分子的相互作用,计算机辅助药物设计等。
付伟,女,博士、副研究员。曾在中科院上海药物所进行两年博士后研究,美国休斯敦大学进行三年博士后研究,西班牙巴塞罗那超级计算中心进行三个半月的访问研究,并与2007年1月回复旦工作。现有硕士研究生一名。研究方向:1.基于结构的抑制剂设计和发现。主要针对G蛋白(GPCR)偶连受体家族,特别是多巴胺(Dopamine)受体,阿片受体等,最终达到治疗中枢神经系统类疾病,如精神分裂症等。2. 分子力学和分子动力学模拟及分子对接研究受体和药物小分子的相互作用3. 计算机辅助药物设计: 三维定量构效关系、分子对接、数据库搜寻及全新药物设计4. 传染病病毒的作用机理研究,特别是波特林毒素的易位机理研究5. 布朗动力学模拟生物大分子之间的相互作用6. 药物分子设计与合成。发表论文三十余篇。现主持项目三项,其中,国家自然科学基金项目一项,博士点新教师基金项目一项,上海市卫生局项目一项。
-
主页访问
3278
-
关注数
0
-
成果阅读
507
-
成果数
10
付伟, Wei Fu, Meng Cui, James M. Briggs, Xiaoqin Huang, Bing Xiong, Yingmin Zhang, Xiaomin Luo, Jianhua Shen, Ruyun Ji, Hualiang Jiang, Kaixian Chen
Biophysical Journal Volume 83 November 2002 2370–2385,-0001,():
-1年11月30日
The recognition of the scorpion toxin maurotoxin (MTX) by the voltage-gated potassium (Kv1) channels, Kv1.1, Kv1.2, and Kv1.3, has been studied by means of Brownian dynamics (BD) simulations. All of the 35 available structures of MTX in the Protein Data Bank (http: //www.rcsb.org/pdb) determined by nuclear magnetic resonance were considered during the simulations, which indicated that the conformation of MTX significantly affected both the recognition and the binding between MTX and the Kv1 channels. Comparing the top five highest-frequency structures of MTX binding to the Kv1 channels, we found that the Kv1.2 channel, with the highest docking frequencies and the lowest electrostatic interaction energies, was the most favorable for MTX binding, whereas Kv1.1 was intermediate, and Kv1.3 was the least favorable one. Among the 35 structures of MTX, the 10th structure docked into the binding site of the Kv1.2 channel with the highest probability and the most favorable electrostatic interactions. From the MTX-Kv1.2 binding model, we identified the critical residues for the recognition of these two proteins through triplet contact analyses. MTX locates around the extracellular mouth of the Kv1 channels, making contacts with its β-sheets. Lys23, a conserved amino acid in the scorpion toxins, protrudes into the pore of the Kv1.2 channel and forms two hydrogen bonds with the conserved residues Gly401(D) and Tyr400(C) and one hydrophobic contact with Gly401(C) of the Kv1.2 channel. The critical triplet contacts for recognition between MTX and the Kv1.2 channel are Lys23(MTX)-Asp402(C)(Kv1), Lys27(MTX)-Asp378(D)(Kv1), and Lys30(MTX)-Asp402(A)(Kv1). In addition, six hydrogen-bonding interactions are formed between residues Lys23, Lys27, Lys30, and Tyr32 of MTX and residues Gly401, Tyr400, Asp402, Asp378, and Thr406 of Kv1.2. Many of them are formed by side chains of residues of MTX and backbone atoms of the Kv1.2 channel. Five hydrophobic contacts exist between residues Pro20, Lys23, Lys30 and Tyr32 of MTX and residues Asp402, Val404, Gly401, and Arg377 of the Kv1.2 channel. The simulation results are in agreement with the previous molecular biology experiments and explain the binding phenomena between MTX and Kv1 channels at the molecular level. The consistency between the results of the BD simulations and the experimental data indicated that our three-dimensional model of the MTX-Kv1.2 channel complex is reasonable and can be used in additional biological studies, such as rational design of novel therapeutic agents blocking the voltage-gated channels and in mutagenesis studies in both the toxins and the Kv1 channels. In particular, both the BD simulations and the molecular mechanics refinements indicate that residue Asp378 of the Kv1.2 channel is critical for its recognition and binding functionality toward MTX. This phenomenon has not been appreciated in the previous mutagenesis experiments, indicating this might be a new clue for additional functional study of Kv1 channels.
-
57浏览
-
0点赞
-
0收藏
-
0分享
-
124下载
-
0评论
-
引用
付伟, Kunqian Yu, , Wei Fu, Hong Liu, Xiaomin Luo, Kai Xian Chen, Jianping Ding, Jianhua Shen, Hualiang Jiang
Biophysical Journal Volume 86 June 2004 3542-3555,-0001,():
-1年11月30日
Based on a homology model of the Kv1.3 potassium channel, the recognitions of the six scorpion toxins, viz. agitoxin2, charybdotoxin, kaliotoxin, margatoxin, noxiustoxin, and Pandinus toxin, to the human Kv1.3 potassium channel have been investigated by using an approach of the Brownian dynamics (BD) simulation integrating molecular dynamics (MD) simulation. Reasonable three-dimensional structures of the toxin-channel complexes have been obtained employing BD simulations and triplet contact analyses. All of the available structures of the six scorpion toxins in the Research Collaboratory for Structural Bioinformatics Protein Data Bank determined by NMR were considered during the simulation, which indicated that the conformations of the toxin significantly affect both the molecular recognition and binding energy between the two proteins. BD simulations predicted that all the six scorpion toxins in this study use their b-sheets to bind to the extracellular entryway of the Kv1.3 channel, which is in line with the primary clues from the electrostatic interaction calculations and mutagenesis results. Additionally, the electrostatic interaction energies between the toxins and Kv1.3 channel correlate well with the binding affinities (-logKds), R2 = 0.603, suggesting that the electrostatic interaction is a dominant component for toxin-channel binding specificity. Most importantly, recognition residues and interaction contacts for the binding were identified. Lys-27 or Lys-28, residues Arg-24 or Arg-25 in the separate six toxins, and residues Tyr-400, Asp-402, His-404, Asp-386, and Gly-380 in each subunit of the Kv1.3 potassium channel, are the key residues for the toxin-channel recognitions. This is in agreement with the mutation results. MD simulations lasting 5 ns for the individual proteins and the toxin-channel complexes in a solvated lipid bilayer environment confirmed that the toxins are flexible and the channel is not flexible in the binding. The consistency between the results of the simulations and the experimental data indicated that our three-dimensional models of the toxin-channel complex are reasonable and can be used as a guide for future biological studies, such as the rational design of the blocking agents of the Kv1.3 channel and mutagenesis in both toxins and the Kv1.3 channel. Moreover, the simulation result demonstrates that the electrostatic interaction energies combined with the distribution frequencies from BD simulations might be used as criteria in ranking the binding configuration of a scorpion toxin to the Kv1.3 channel.
-
44浏览
-
0点赞
-
0收藏
-
0分享
-
126下载
-
0评论
-
引用
付伟, Wei Fu, Hong-Xing Zhang, Ji-Kang Feng, Wei Li
Can. J. Chem. 79: 1366-1375(2001),-0001,():
-1年11月30日
to evaluate the second-order nonlinear susceptibilities for a series of fulleropyrrolidine-tetrathiafulvalene(C60PY-TTF) dyads, C60PY, and C60PY-(CH=CH)n-TTF (n = 0-6). The equilibrium geometries, electronic structures, and UV-vis spectra of these C60PY-TTFs D-B-A dyads were determined by using ZINDO methods. On the basis of electronic spectra, we calculated the β for the dyads using the ZINDO-SOS expression, and found that these dyads have relatively large β. The calculated values of p are 48.78, 62.34, 97.90, 123.24, 183.78, 189.43, 193.45, 195.82 × 10-30 esu for C60PY and C60PY-(CH=CH)n-TTF (n=0-6), respectively, which shows the enhancing effect when TTF is introduced. The β significantly increases as n increases from 0-3; and it tends to be saturated in the end.
ZINDO-SOS, CI, structure, spectra, C60PY-TTF
-
39浏览
-
0点赞
-
0收藏
-
0分享
-
96下载
-
0评论
-
引用
付伟, Wei Fu, Ji-Kang Feng, Ge-Bo Pan, Xiang Zhang
Theor Chem Acc (2001) 106: 241-250,-0001,():
-1年11月30日
The equilibrium geometries, electronic structures and UV-vis spectra of a series of spiroannelated quinone-type methanofullerenes have been determined by using Zerner’s intermediate neglect of differential overlap method. The results show that between fullerene and the addend there exists a special interaction, “periconjugation”, which results in through-space orbital interactions. The calculated UV-vis spectra are in good agreement with experiments. On the basis of the electronic spectra, the β values are calculated. The results show that spiroannelated quinone-type methanofullerenes have quite large β values. We attribute the large β values to both the charge transfer from C60 to benzoquinone and on the C60 three-dimensional conjugated sphere.
Spiroannelated quinone-type methanofullerenes, Geometry, UV-vis spectra, Nonlinear second-order susceptibilities
-
47浏览
-
0点赞
-
0收藏
-
0分享
-
151下载
-
0评论
-
引用
付伟, Wei Fu, Ji-Kang Feng, Ge-Bo Pan
Journal of Molecular Structure (Theochem) 545 (2001) 157-165,-0001,():
-1年11月30日
Using density functional theory and ZINDO methods, the structures, molecular orbitals and electronic spectra of a series of spirobifluorenes were investigated, in which two identical push-pull type chromophores are connected via an insulating carbon. Based on the correct electronic spectra, according to the sum-over-states formula, the calculation program was devised and nonlinear third-order optical susceptibilities were calculated. The results show a good agreement between the calculation and experiment. The calculated nonlinear third-order susceptibility γ of the spirobifluorenes are about six times as large as those of the corresponding mono-fluorenes without an increase of λmax. Since electronic coupling between monomer units in the spirobifluorenes is negligible owing to symmetry, we attribute the large enhancement to the spiroconjugation. Thus, we conclude that derived spirobifluorenes will be a hopeful type of third-order nonlinear optical material from the standpoint of the high transparency and relatively large γ value.
Spiroconjugation, Third-order nonlinear optical properties
-
49浏览
-
0点赞
-
0收藏
-
0分享
-
219下载
-
0评论
-
引用
【期刊论文】给体-桥-受体型系列C60吡咯/二茂铁的电子结构及二阶非线性光学性质的理论研究
付伟, 封继康, 崔勐, 苏忠民, 任爱民
化学学报2000年第58卷第9期,1112-1119/ACTA CHIMICA SINICA Vol.58, 2000, No.9, 1112-1119,-0001,():
-1年11月30日
用INDO/2和INDO/CI方法,计算了系列给体-桥-受体(D-B-A)型C60吡咯/二茂铁(C60PY/Fc)的结构和电子光谱,计算结果和实验结果一致,在正确的光谱基础上,用INDO/CI-SOS公式计算了该系列分子的二阶非线性光学系数βijk,βμ。考察了分子电子结构对βμ影响的微观本质。
C60吡咯/二茂铁, 电子结构, 二阶非线性光学性质, 电荷转移
-
65浏览
-
0点赞
-
0收藏
-
0分享
-
64下载
-
0评论
-
引用
付伟, Wei Fu, , Jianhua Shen, Xiaomin Luo, Weiliang Zhu, Jiagao Cheng, Kunqian Yu, James M. Briggs, Guozhang Jin, Kaixian Chen, Hualiang Jiang
Biophysical Journal Volume 93 September 2007 1431–1441,-0001,():
-1年11月30日
(–)–Stepholidine (SPD), an active ingredient of the Chinese herb Stephania, is the first compound found to have dual function as a dopamine receptor D1 agonist and D2 antagonist. Insights into dynamical behaviors of D1 and D2 receptors and their interaction modes with SPD are crucial in understanding the structural and functional characteristics of dopamine receptors. In this study a computational approach, integrating protein structure prediction, automated molecular docking, and molecular dynamics simulations were employed to investigate the dual action mechanism of SPD on the D1 and D2 receptors, with the eventual aim to develop new drugs for treating diseases affecting the central nervous system such as schizophrenia. The dynamics simulations revealed the surface features of the electrostatic potentials and the conformational “open-closed” process of the binding entrances of two dopamine receptors. Potential binding conformations of D1 and D2 receptors were obtained, and the D1-SPD and D2-SPD complexes were generated, which are in good agreement with most of experimental data. The D1-SPD structure shows that the K-167_EL-2-E-302_EL-3 (EL-2: extracellular loop 2; EL-3: extracellular loop 3) salt bridge plays an important role for both the conformational change of the extracellular domain and the binding of SPD. Based on our modeling and simulations, we proposed a mechanism of the dual action of SPD and a subsequent signal transduction model. Further mutagenesis and biophysical experiments are needed to test and improve our proposed dual action mechanism of SPD and signal transduction model.
-
43浏览
-
0点赞
-
0收藏
-
0分享
-
151下载
-
0评论
-
引用
【期刊论文】Simulating the Interactions of Toxins with K+ Channels
付伟, Xiaoqin Huang, , Hong Liu, Meng Cui, Wei Fu, Kunqian Yu, Kaixian Chen, Xiaomin Luo, Jianhua Shen, Hualiang Jiang
Current Pharmaceutical Design, 2004, 10, 1057-1067,-0001,():
-1年11月30日
Toxins have been important tools to characterize the structures and functions of K+ channels in recent years due to their unique blockage of the K+ current and other physiological functions to the K+ channels, especially the voltage-gated K+ channels. Knowledge of the interacting surfaces between the toxins and the channels has been accumulated both from biological explorations and theoretical simulations. It has been found that the electrostatic potentials act as the driving force for the recognition of the toxins with the channels, and the orientation of the toxins over the channels follows the direction of the dipole moment. The binding site is composed most of the conservative residues of the negatively charged rings of Asp/Glu and residues around the edge of the central pore. The selectivity mainly comes from the type and distribution of the positive charged residues, and the whole topologies of the toxins. Based on the molecular determinants of the complex formation, and taking advantage of the structure-based methodologies of molecular design, it is hopefully to develop new generation of lead compounds specifically binding with subtypes of K+ channels.
Toxins, K+, channels, Brownian dynamics, electrostatic potential, structure-function relationships.,
-
43浏览
-
0点赞
-
0收藏
-
0分享
-
149下载
-
0评论
-
引用
【期刊论文】系列新推拉型多环共轭分子二阶非线性光学性质的理论研究
付伟, 封继康, 任爱民, 孙秀云, 金宏威, 王江洪, 沈玉全
高等学校化学学报2000年4月第21卷第4期/CHEMICAL JOURNAL OF CHINESE UNIVERSITIES Vol.21, No.4, 2000,-0001,():
-1年11月30日
在AM1和ZINDO方法基础上,按完全态求和(SOS)公式编制了计算分子二阶非线性光学系数βijk和βμ的程序,研究了一系列新推拉型多环共轭分子的结构、光谱和二阶非线性光学系数β(-2ω,ω,ω)和β(0,0,0)。考察了分子共轭链长、分子骨架和给电子取代基对βμ的影响,并设计了具有最大βμ的新型非线性光学材料分子。
非线性光学材料, 分子设计, 二阶非线性光学系数
-
59浏览
-
0点赞
-
0收藏
-
0分享
-
127下载
-
0评论
-
引用
【期刊论文】不对称二苯乙炔系列衍生物的二阶非线性光学性质的ZINDO-SOS研究
付伟, 封继康, 任爱民, 崔勐, 孙秀云, 李耀先
化学学报/ACTA CHIMICA SINICA 1999,57,1075-1080,-0001,():
-1年11月30日
在ZINDO方法基础上,按完全态求和(SOS)公式编制了计算分子二阶非线性光学系数βijk,βμ的程序;研究了不对称二苯乙炔系列衍生物的结构和非线性光学性质;计算了不对称二苯乙炔系列衍生物的UV光谱,偶极矩,βμ,β0,μβ,μβ0,及激发态电荷转移;考察了分子共轭链长、给电子基团对βμ的影响。并对上述结果在微观上给予了解释。
不对称二苯乙炔系列衍生物, 二阶非线性光学系数, 电荷转移
-
61浏览
-
0点赞
-
0收藏
-
0分享
-
60下载
-
0评论
-
引用