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药物发现与设计中心
中心简介
陈凯先研究组
蒋华良研究组
朱维良研究组
沈建华研究组
顾健德研究组
许叶春研究组
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朱维良研究组
朱维良研究组

  

  课题组成立于2004年,现有科研人员5名,技术人员2名,研究生 5 名,联合养研究生3名。

  

 

  主要研究领域为药物设计、计算化学及计算生物学,特别注重方法发展、软件开发及应用研究相结合的研究工作。具体研究内容包括:

 

  1、针对重大疾病的药物先导化合物发现和优化。

  应用各种药物设计方法,如分子对接、药效团、骨架跃迁、定量构效关系等,针对抗肿瘤、抗糖尿病、抗病毒以及抗结核的分子靶标,开展活性化合物的发现、设计和结构优化研究。目前重点开展B-Raf激酶V600E突变体抑制剂、二肽基肽酶-4(DPP4)抑制剂、核糖核苷酸还原酶(RR)抑制剂、游离脂肪酸受体GPR40拮抗剂、登革病毒蛋白酶(NS2B-NS3)抑制剂、结核杆菌乙酰羟酸合成酶(AHAS)抑制剂、CDK抑制剂等的发现与优化研究。

 

 

  2、分子间作用力及其在药物设计中的应用研究。

  除了常见的范德华力、静电作用和氢键外,分子间作用力还包括阳离子-p及卤键等作用。尤其是卤键,近年来在药物设计领域引起了极大的兴趣。我们运用量子力学结合分子力学的方法探索了阳离子-p和卤键作用本质,并在磷酸二酯酶5(PDE5)抑制剂等活性化合物的优化中引入这些分子间作用力,提高了先导化合物的活性。

 

 

  3、蛋白质结构功能的分子动力学模拟研究。

  对一系列膜蛋白、酶、核糖核酸(如PAFR、GPR40、5-HT2C、多巴胺受体、铵离子转运蛋白、登革病毒蛋白酶及β-分泌酶)等具有重要生物学功能的生物大分子体系开展分子动力学模拟,解释了一系列重要的实验现象及结构功能关系,并将这些信息应用到药物设计中。

 

 

课题组成员合影

 

    

 

 

   课题组成立以来共发表SCI研究论文100余篇,递交专利申请34件,应邀在国内外学术大会上做报告30余次,参加编写及翻译专著5部。近5年发表的部分论文如下:

  1. Jing Deng, Ning Li, Hongchuan Liu, Zhili Zuo, Oi Wah Liew, Weijun Xu, Gang Chen, Xiankun Tong, Wei Tang*, Jin Zhu, Jianping Zuo, Hualiang Jiang, Cai-Guang Yang*, Jian Li*, Weiliang Zhu*, Discovery of Novel Small Molecule Inhibitors of Dengue Viral NS2BNS3 Protease Using Virtual Screening and Scaffold Hopping, J. Med. Chem. 2012, 55, 6278 - 6293
  2. Yunxiang Lu, Yingtao Liu, Haiying Li, Xiang Zhu, Honglai Liu, and Weiliang Zhu, Energetic Effects between Halogen Bonds and Anion-π or Lone Pair-π Interactions: A Theoretical Study, The Journal of Physical Chemistry A, 2012 116 (10), 2591-2597
  3. Jinwei Wu, Peng Sun, Xiaodong Zhang, Hong Liu, Hualiang Jiang, Weiliang Zhu, Heyao Wang*. Inhibition of GPR40 protects MIN6 β-cells from palmitate-induced ER stress and apoptosis. Journal of Cellular Biochemistry. 2012 Apr;113(4):1152-8.
  4. Di Wang, Fei Wang, Yexiong Tan, Liwei Dong, Lei Chen, Weiliang Zhu*, Hongyang Wang*, Discovery of potent small molecule inhibitors of DYRK1A by structure-based virtual screening and bioassay, Bioorganic & Medicinal Chemistry Letters, 2012, 22, 168–171
  5. Yunxiang Lu*, Haiying Li, Xiang Zhu, Honglai Liu, Weiliang Zhu, Effects of solvent on weak halogen bonds: Density functional theory calculations, International Journal of Quantum Chemistry, 2011 DOI: 10.1002/qua.23125
  6. Xue-lian Zhu, Hai-yan Cai, Zhi-jian Xu, Yong Wang, He-yao Wang, Ao Zhang and Wei-liang Zhu*. Classification of 5-HT(1A) receptor agonists and antagonists using GA-SVM method. Acta Pharmacol Sin., 2011, 32, 1424–1430
  7. Lu Junming, Lu Yunxiang, Yang Subin, Zhu Weiliang*, Theoretical and crystallographic data investigations of noncovalent S···O interactions, Structural Chemistry, 2011, 24, 757-763
  8. Lu Y*, Li H, Zhu X, Zhu W, Liu H. How does halogen bonding behave in solution? A theoretical study using implicit solvation model. J. Phys Chem A. 2011, 115(17),4467-75
  9. Zhijian Xu1, Zheng Liu1, Tong Chen1, Tiantian Chen, Zhen Wang, Guanghui Tian, Jing Shi, Xuelan Wang, Yunxiang Lu, Xiuhua Yan, Guan Wang, Hualiang Jiang, Kaixian Chen, Shudong Wang, Yechun Xu*, Jingshan Shen*, Weilang Zhu*, Utilization of Halogen Bond in Lead Optimization: a Case Study of Rational Design of Potent Phosphodiesterase Type 5 (PDE5) Inhibitors, J. Med. Chem., 2011, 54 (15), 5607–5611
  10. Junming Lu, Bo Zhang, Qingming Deng, Jinan Wang,Yunxiang Lu*,Weiliang Zhu*, The Nature and Magnitude of Specific Halogen Bonds between Iodo-perfluorobenzene and Heterocyclic Systems, International Journal of Quantum Chemistry, 2011, 111, 2352-2358.
  11. Jinan Wang, Huaiyu Yang, Zhili Zuo, Xiuhua Yan, Yong Wang, Xiaomin Luo, Hualiang Jiang, Kaixian Chen, Weiliang Zhu*, Molecular Dynamics Simulations on the Mechanism of Transporting Methylamine and Ammonia by Ammonium Transporter AmtB,J. Phys. Chem. B, 2010, 114, 15172–15179.
  12. Weijun Xun; Gang Chen; Weiliang Zhu*, Zhili Zuo*, Molecular docking and Structure-Activity Relationship Studies on Benzothiazole based non-peptidic BACE-1 inhibitors, Bioorganic & Medicinal Chemistry Letters, 2010, 20, 6203-6207
  13. Xiaodong Zhang, Guirui Yan, Yiming Li, Weiliang Zhu* and Heyao Wang*, DC260126, a small-molecular antagonist of GPR40, improves insulin tolerance but not glucose tolerance in obese Zucker rats, Biomedicine & Pharmacotherapy, 2010, 64(9), 647-651
  14. Weijun Xu, Gang Chen, Hualiang Jiang, Weiliang Zhu*, Zhili Zuo*, Identification of a sub-micromolar Nonpeptide Inhibitor of β-secretase with low neural cytotoxicity through In-silico Screening, Bioorganic & Medicinal Chemistry Letters, 2010, 20, 5763-5766.
  15. Haiyan Cai, Guirui Yan, Xiaodong Zhang, Olena Gorbenko, Heyao Wang*, Weiliang Zhu*, Discovery of highly selective inhibitors of human fatty acid binding protein 4 (FABP4) by virtual screening, Bioorganic & Medicinal Chemistry Letters, 2010, 20(12), 3675-9
  16. Junming Lu, Yunxiang Lu*, Weiliang Zhu, Novel halogen bonding interactions between MH2 (M = Mg, Be) and HX (X = Cl, Br, I) molecules,Journal of Molecular Structure: THEOCHEM, 2010, 952, 84-89.
  17. Shao-Yong Lu, Yong-Jun Jiang*, Jing Lv, Tian-Xing Wu, Qing-Sen Yu, Wei-Liang Zhu,* Molecular docking and molecular dynamics simulation studies of GPR40 receptor–agonist interactions , Journal of Molecular Graphics and Modelling, 2010, 28, 766–774.
  18. Yunxiang Lu, Yong Wang and Weiliang Zhu*, Nonbonding interactions of organic halogens in biological systems: implications for drug discovery and biomolecular design, Physical Chemistry Chemical Physics, 2010, 12, 4543 - 4551.
  19. Zhi Chen, Guanghui Tian, Zhen Wang, Hualiang Jiang, Jingshan Shen*, and Weiliang Zhu*, Multiple Pharmacophore Models Combined with Molecular Docking: A Reliable Way for Efficiently Identifying Novel PDE4 Inhibitors with High Structural Diversity, J. Chem. Inf. Model., 2010, 50, 615-625
  20. Nan Li, Fei Wang, Siqiang Niu, Ju Cao, Kaifeng Wu, Youqiang Li, Nanlin Yin, Xuemei Zhang, Weiliang Zhu and Yibing Yin, Discovery of novel inhibitors of Streptococcus pneumoniae based on the virtual screening with the homology-modeled structure of histidine kinase (VicK), BMC Microbiology, 2009, 27, 129.
  21. Hui Hu, Lingyan He, Zhen Gong, Ning Li, Yina Lu Qiwei Zhai, Hong Liu, Hualiang Jiang, Weiliang Zhu,* Heyao Wang*, A novel class of antagonists for the FFAs receptor GPR40, Biochem Biophys Res Commun, 2009, 390(3), 557-63
  22. Kunqian Yu, Cheng Luo, Guangrong Qin, Zhijian Xu, Ning Li, Hong Liu, Xu Shen, Jianpeng Ma, Qinghua Wang, Caiguang Yang, Weiliang Zhu*, Hualiang Jiang*, Why are oseltamivir and zanamivir effective against the newly emerged influenza A virus (A/H1N1)?, Cell Research, 2009, 10, 1038
  23. Yunxiang Lu, Yong Wang, Zhijian Xu, Xiuhua Yan, Xiaoming Luo, Hualiang Jiang, and Weiliang Zhu*, C−X•••H Contacts in Biomolecular Systems: How They Contribute to Protein-Ligand Binding Affinity? J. Phys. Chem. (B), 2009, 113, 12615–12621.
  24. Yunxiang Lu, Ting Shi, Yong Wang, Huaiyu Yang, Xiuhua Yan, Xiaoming Luo, Hualiang Jiang, Weiliang Zhu*, Halogen Bonding — A Novel Interaction for Rational Drug Design, J. Med. Chem., 2009, 52, 2854–2862.
  25. Zhili Zuo, Oi Wah Liew, Gang Chen, Pek Ching Jenny Chong, Siew Hui Lee, Kaixian Chen, Hualiang Jiang, Chum Mok Puah*, Weiliang Zhu*, Mechanism of NS2B-mediated activation of NS3pro in Dengue Virus: Molecular Dynamics Simulations and Bioassay Studies, J. Virology, 2009, 83, 1060-1070
  26. Weijun Xu, Gang Chen, Oi Wah Liew, Zhili Zuo*, Hualiang Jiang, Weiliang Zhu*, Novel non-peptide b-secretase inhibitors derived from structure-based virtual screening and bioassay Bioorganic & Medicinal Chemistry Letters, 2009, 19, 3188–3192
  27. Mingyue Zheng, Xiaomin Luo, Qiancheng Shen,Yong Wang, Yun Du, Weiliang Zhu and Hualiang Jiang, Site of Metabolism (SOM) Prediction for Six Biotransformations Mediated by Cytochromes P450, Bioinformatics, 2009, 25(10), 1251–1258
  28. 李波,朱维良*,陈凯先*,小檗碱及其衍生物的研究进展,药学学报,2008,43,773-787
  29. Lingyan He, Jiagao Cheng, Tao Wang, Caimei Li, Zhen Gong, Hong Liu*, Bu-Bing Zeng*, Hualiang Jiang, Weiliang Zhu*, Cation–p complexes formed between cyclooctatetraene and alkaline earth metals: Predicted and recorded NMR features, Chemical Physics Letters, 2008, 462, 45–48.
  30. Zhi-Li ZUO, Gang CHEN, Xiao-Min LUO, Chum-Mok PUAH*, Wei-Liang ZHU*, Kai-Xian CHEN, Hua-Liang JIANG. Pharmacophore-Directed Homology Modeling and MD Simulation of G-protein-Coupled Receptor: Study of Possible Binding Modes of the 5-HT2C Receptor Agonists, Acta Biochimica et Biophysica Sinica, 2007, 39, 413-422.
  31. Wei Fu1,3, Jianhua Shen1, Xiaomin Luo1, Weiliang Zhu1*, Jiagao Cheng1, Kunqian Yu1, James M. Briggs2, Guozhang Jin1, Kaixian Chen1 and Hualiang Jiang1,4*,Dopamine D1 Receptor Agonist and D2 Receptor Antagonist Effects of the Natural Product (-)-Stepholidine (SPD): Molecular Modeling and Dynamics Simulations, Biophysics Journal,2007, 93, 1431-1441
  32. Zhili Zuo, Chen Gang, Hanjun Zou, Puah Chum Mok, Weiliang Zhu*, Kaixian Chen, Hualiang Jiang,. Why does β-secretase zymogen possess catalytic activity? Molecular modeling and molecular dynamics simulation studies, Computational Biology and Chemistry, 2007, 31, 186–195
  33. Chunshan Gui, Weiliang Zhu*, Gang Chen, Xiaomin Luo, Oi Wah Liew, Chum Mok Puah, Kaixian Chen, and Hualiang Jiang*, Understanding the Regulation Mechanisms of PAF Receptor by Agonists and Antagonists: Molecular Modeling and Molecular Dynamics Simulation Studies, Proteins: Structure, Function, and Bioinformatics, 2007, 67, 41–52
  34. Jiagao Cheng, Zhen Gong, Weiliang Zhu*, Yun Tang, Weihua Li, Zhong Li, Hualiang Jiang*, Cation sitting in aromatic cages: ab initio computational studies on tetramethylamonium–(benzene)n (n=3-4) complexes, JOPC, 2007, 20, 448-453
  35. Huaiyu Yang, Yechun Xu, Weiliang Zhu*, Kaixian Chen and Hualiang Jiang*, Detailed Mechanism for AmtB Conducting NH4+/NH3: Molecular Dynamics Simulations,  Biophysics Journal, 2007, 92, 877-885  

  

  课题组承担的科研任务包括中国科学院“百人计划”课题、国家高技术研究发展计划 (863 计划 ) 课题、 国家自然科学基金面上项目,并参加自然科学基金创新研究群体项目、国家重点基础研究发展计划 973 计划课题、中科院方向性课题等研究工作。

 

研究室组织结构
  

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