黄牛博士

研究生教育

黄牛博士

北京生命科学研究所高级研究员

Niu Huang, Ph.D. Associate Investigator, NIBS, Beijing, China

Phone：010-80726688-8570

Fax： 010-80726689

E-mail：huangniu@nibs.ac.cn

研究概述：

近年来，生物学领域的研究进展极大地加深了我们对和疾病密切相关的分子靶标的认识。然而，如何有效地利用这些生物学信息，进而针对疾病靶标来设计治疗性药物，还需要我们从原子水平上来掌握生物大分子的三维结构和生物功能之间的关系。我们将进一步开发基于物理学原理的计算化学理论和分子模拟技术，来研究在分子识别过程（蛋白－蛋白，蛋白－核酸和蛋白－配体相互作用）中的自由能和空间构象的变化，从而指导蛋白质结构和功能的改造，以及加速新药的设计与开发。我们将充分利用本实验室在大分子模拟和小分子设计方面的条件和经验，积极促进物理和计算科学在生物学中的应用，同时探索高性能科学计算（High-performance Computing, HPC）的方法学研究。

http://www.huanglab.org.cn

主要研究方向

一．改进分子对接技术和提高打分函数的精度

在已知受体结构和作用位点的情况下，分子对接技术（Molecular Docking）可被用于自动匹配受体结合腔穴和数据库中的小分子化合物，并预测与受体结合作用最强的一组化合物，来进行活性测试以节省新型先导化合物开发的周期和成本。我们将系统地研究和改进目前计算受体和配体结合自由能方法中的局限性因素，例如诱导契合、去溶剂化效应、熵效应，以及静电作用的精确计算等，来提高虚拟筛选的成功率。

二．研究可被配体调控的蛋白－蛋白相互作用

蛋白－蛋白相互作用（Protein-Protein Interactions, PPIs）在许多生物学过程中起关键性作用。然而，基于这类重要分子靶标开发小分子药物的成功率非常低。我们认为其中的一个重要原因是PPIs的成药性（Druggability）与其结构的内在柔性密切相关，因此我们将利用多种构象搜寻手段来模拟PPIs界面的动态构象变化以及相关的自由能变化，预测可能的小分子结合腔穴，并且定量分析和评估这些结合位点的成药性，从而为下一步的虚拟筛选奠定基础。

Research Description:

The opening of the 21st century has marked with the sequencing of the human genome. Today, the understanding of the sequence and structure of biologically relevant targets is growing rapidly and researchers from many disciplines, physics and computational science in particular, are making significant contributions to modern biology and drug discovery. State-of-the-art computational chemistry and molecular modeling techniques can be applied to study a wide range of chemical and biological systems of interest, which enable us to acquire information not obtainable by experimental techniques, to investigate structural phenomena at the atomic level and to identify novel compounds with desired biological characteristics. Our laboratory is interested in developing and applying computational techniques to study the structural and energetic basis of molecular recognition (i.e., protein-protein, protein-DNA and protein-ligand interactions). Aside from its fundamental biological interest, such theoretical studies have tremendous practical values of which one of the most important is structure-based drug design.

Publications

1.	Dong T, Li C, Wang X, Dian L, Zhang X, Li L, Chen S, Cao R, Li L, Huang N, He S, Lei X. Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine. Nat Commun. 2015, 6:6522.
2.	Yu zhou and Niu Huang. Binding site druggability assessment in fragment-based drug design. Methods Mol. Biol. 2015, 1289:13-21.
3.	Yao Q, Zhang L, Wan X, Chen J, Hu L, Ding X, Li L, Karar J, Peng H, Chen S, Huang N, Rauscher FJ, Shao F. (2014) Structure and Specificity of the Bacterial Cysteine Methyltransferase Effector NleE Suggests a Novel Substrate in Human DNA Repair Pathway. PLoS Pathog. 2014, 10(11): e1004522.
4.	Yao Q, Lu Q, Wan X, Song F, Xu Y, Hu M, Zamyatina A, Liu X, Huang N, Zhu P, Shao F. A structural mechanism for bacterial autotransporter glycosylation by a dodecameric heptosyltransferase family. Elife. 2014, Oct 13;3. doi: 10.7554/eLife.03714.
5.	Ran Cao, Niu Huang and Yanli Wang. Evaluation and application of MD-PB/SA in structure-based hierarchical virtual screening. J Chem Inf Model. 2014, 54:1987-96.
6.	Deng M, Lu Z, Zheng J, Wan X, Chen X, Hirayasu K, Sun H, Lam Y, Chen L, Wang Q, Song C, Huang N, Gao GF, Jiang Y, Arase H, Zhang CC. A motif in LILRB2 critical for Angptl2 binding and activation. Blood. 2014, 124:924-35.
7.	Yu Zhou, Chao Wu, Lifeng Zhao and Niu Huang. Exploring the early stages of the pH-induced conformational change of influenza hemagglutinin. Proteins. 2014, 82:2412-28.
8.	Hanzi Sun, Lifeng Zhao, Shiming Peng and Niu Huang. Incorporating Replacement Free Energy of Binding-site Waters in Molecular Docking. Proteins. 2014, 82:1765-76.
9.	Wei Li, Xiaobo Wan, Wei Zhang, Fanqi Zeng, Yanli Wang, Yuting Xie, Li Li and Niu Huang. More than just GPCR Ligand: Structure-based Discovery of Thioridazine Derivatives as Pim-1 Kinase Inhibitors. Med. Chem.Commun. 2014, 5:507-511.
10.	Ran Cao, Wei Li, Hanzi Sun, Yu Zhou and Niu Huang. Computational chemistry in structure-based drug design. Acta Pharmaceutica Sinica. 2013, 48:1041-1052.
11.	Shiming Peng, Yu Zhou and Niu Huang. Improving the accuracy of pose prediction in molecular docking via structural filtering and conformational clustering. Chinese Chem. Lett. 2013, 24:1001-1004.
12.	Fanqi Zeng, Shiming Peng, Li Li, Libing Mu, Zhenghua Zhang, Zhiyuan Zhang and Niu Huang. HAT off: structure-based identification of drug-like inhibitors of p300 histone acetyltransferase. Acta Pharmaceutica Sinica. 2013, 48:700-708.
13.	Xiaobo Wan, Yue Ma, Christopher L. McClendon, Lily Jun-shen Huang and Niu Huang. Ab Initio Modeling and Experimental Assessment of Janus Kinase 2 (JAK2) Kinase-Pseudokinase Complex Structure. PLoS Comp. Biol. 2013, 9: e1003022.
14.	Xiaobo Wan, Wei Zhang, Li Li, Yuting Xie, Wei Li and Niu Huang. A New Target for An Old Drug: Identifying Mitoxantrone as a Nanomolar Inhibitor of PIM1 Kinase via Kinome-wide Selectivity Modeling. J. Med. Chem. 2013, 56:2619-29.
15.	Yao Wu, Xiaodong Dai, Niu Huang* and Lifeng Zhao. A partition function-based weighting scheme in force field parameter development using ab initio calculation results in global configurational space. J. Comp. Chem.* 2013, 34:1271-82.
16.	Yanli Wang, Minyu Liu, Ran Cao, Ming Yin, Riuhua Xiao, Quanhai Liu and Niu Huang. A Soluble Bis-chelated Gold(I) Diphosphine Compound with Strong Anticancer Activity and Low Toxicity. J. Med. Chem. 2013, 56: 1455-66.
17.	Qing Yao, Jixin Cui, Jiayi Wang, Ting Li, Xiaobo Wan, Tianming Luo, Yi-Nan Gong, Ying Xu, Niu Huang and Feng Shao. Structural mechanism of ubiquitin and NEDD8 deamidation catalyzed by bacterial effectors that induce macrophage-specific apoptosis. Proc. Natl. Acad. Sci. U S A. 2012, 109:20395-400.
18.	Ran Cao, Minyu Liu, Min Yin, Quanhai Liu, Yanli Wang and Niu Huang. Discovery of Novel Tubulin Inhibitors via Structure-Based Hierarchical Virtual Screening. J. Chem. Inf. Model. 2012, 52:2730-40.
19.	Shiming Peng, Xingyu Lin, Zongru Guo, Niu Huang. Identifying Multiple-Target Ligands via Computational Chemogenomics Approaches. Curr. Top. Med. Chem. 2012, 12:1363-1375.
20.	Xingyu Lin, Xiping Huang, Gang Chen, Ryan Whaley, Shiming Peng, Yanli Wang, Guoliang Zhang, Shaohui Wang, Xiang Wang, Brian Roth, Niu Huang. Life Beyond Kinases: Structure-Based Discovery of Sorafenib as Nanomolar Antagonist of 5-HT Receptors. J. Med. Chem. 2012, 55:5749-59.(Selected by F1000 Pharmacology & Drug Discovery, Congreve M: 2012. http://f1000.com/717951322 ).
21.	Andrew Christofferson and Niu Huang. How to Benchmark Methods for Structure-Based Virtual Screening of Large Compound Libraries. Methods in Molecular Biology. 2012. 819:187-95. Book
22.	Lifeng Zhao, Chuanjie Wu and Niu Huang. Mutual Solubilities Study for Binary Mixtures of Dipropylene Glycol Dimethyl Ether and Water via Molecular Dynamics Simulation and AMOEBA Polarizable Force Field. Fluid. Phase. Equilib. 2011, 310: 32-8.
23.	Andrew Christofferson, Lifeng Zhao, Hanzi Sun, Zhen Huang and Niu Huang. Theoretical Studies of the Base Pair Fidelity of Selenium-modified DNA. J. Phys. Chem B. 2011, 115:10041-8.
24.	Qiang Pei, Andrew Christofferson, Hui Zhang, Jijie Chai, Niu Huang, Computational Investigation of the Enzymatic Mechanisms of Phosphothreonine Lyase, Biophysical Chemistry. 2011;157(1-3):16-23.
25.	Niu Huang and Matthew P. Jacobson. Binding-Site Assessment by Virtual Fragment Screening. PLoS ONE. 2010, 5: e10109
26.	John Irwin, Brian Shoichet, Michael Mysinger, Niu Huang, Francesco Colizzi, Pascal Wassam and Yiqun Cao. Automated docking screens: a feasibility study. J. Med. Chem. 2009, 52:5712-20
27.	Chaya S. Rapp, Cheryl Schonbrun, Matthew P. Jacobson, Chakrapani Kalyanaraman and Niu Huang. Automated Site Preparation in Rescoring of Receptor Ligand Complexes. Proteins. 2009, 77:52-61
28.	Qing Yao , Jixin Cui , Yongqun Zhu , Guolun Wang , Liyan Hu , Chengzu Long , Ran Cao , Xinqi Liu , Niu Huang , She Chen , Liping Liu and Feng Shao. A bacterial type III effector family uses the papain-like hydrolytic activity to arrest the host cell cycle. Proc. Natl. Acad. Sci. U S A. 2009, 106:3716-3721
29.	Zhiwei Huang, Yingcai Feng, Xiaojing Wu, Xiaojun Wang, Xingguo Xiao, Wenhui Li, Niu Huang, Lichuan Gu, Guangming Zhong and Jijie Chai. Structural and biochemical mechanisms of the catalysis, activation and inhibition of CPAF (Chlamydial Protease/Proteasome-like Activity Factor). Cell Host & Microbe. 2008, 4: 529-542
30.	Niu Huang and Brian Shoichet. Exploring Ordered Waters in Molecular Docking. J. Med. Chem. 2008, 51:4862-4865.
31.	Linjie Chen, Huayi Wang, Jie Zhang, Lichuan Gu, Niu Huang, Jian-Min Zhou and Jijie Chai. Structural basis for the catalytic mechanism of phosphothreonine lyase. Nat. Struct. Mol. Biol. 2008, 15:101-102
32.	Niu Huang and Matthew P. Jacobson. Physics-based Methods for Studying Protein-Ligand Interactions. Curr. Opin. Drug Discov. Devel. 2007, 10:325-331.
33.	Niu Huang, John Irwin and Brian Shoichet. Benchmarking Sets for Molecular Docking. J. Med. Chem. 2006, 49: 6789-6801.
34.	Niu Huang, Chakrapani Kalyanaraman, Katarzyna Bernacki and Matthew P. Jacobson. Ligand Binding Free-energy Calculations via Physics-based Scoring Methods. Phys. Chem. Chem. Phys. 2006, 8: 5166-5177.
35.	Nilesh K. Banavali, Niu Huang and Alexander D. MacKerell, Jr. Conserved Patterns in Backbone Torsion Changes Allow For Single Base Flipping from Duplex DNA with Minimal Distortion of the Double Helix. J. Phys. Chem. B. 2006, 110: 10997-11004.
36.	Niu Huang, Chakrapani Kalyanaraman, John Irwin, Matthew P. Jacobson. Physics-based Scoring of Protein-ligand Complexes: Enrichment of known inhibitors in Large-Scale Virtual Screening. J. Chem. Inf. Model. 2006, 46: 243-253.
37.	Victor M. Anisimov, Guillaume Lamoureux, Igor V. Vorobyov, Niu Huang, Benoit Roux, Alexander D. MacKerell, Jr. Determination of Electrostatic Parameters for a polarizable Force Field Based on the Classical Drude Oscillator. J. Chem. Theory. Comp. 2005, 1: 153-168.
38.	Niu Huang and Alexander D. MacKerell, Jr. Specificity in protein-DNA interactions: Energetic recognition by the (cytosine-C5)-methyltransferase from HhaI. J. Mol. Biol. 2005, 345: 265-274.
39.	John R. Horton, Gary Ratner, Nilesh K. Banavali, Niu Huang, Yongseok Choi, Martin A. Maier, Victor E. Marquez, Alexander D. MacKerell, Jr., Xiaodong Cheng. Caught in the Middle of the Act: Visualization of a Putative Transition State During DNA Base Flipping. Nucl. Acids. Res. 2004, 32: 3877-3886.
40.	Niu Huang, Ashish Nagarsekar, Guanjun Xia, Jun Hayashi and Alexander D. MacKerell, Jr. Identification of Non-Phosphate-Containing Small Molecular Weight Inhibitors of the Tyrosine Kinase p56 Lck SH2 Domain via in Silico Screening against the pY+3 Binding Site. J. Med. Chem. 2004, 47: 3502-3511.
41.	Niu Huang and Alexander D. MacKerell, Jr. Atomistic view of Base flipping in DNA. Phil. Trans. Roy. Soc. Lond. Series A. 2004, 362: 1-22.
42.	Hui Peng, Niu Huang*, Jing Qi, Ping Xie, Chen Xu, Jianxiang Wang and Chunzheng Yang. Identification of novel inhibitors of BCR-ABL tyrosine kinase via virtual screening. Bioorg. Med. Chem. Lett. 2003, 13: 3693-3699. equal contribution
43.	Niu Huang, Nilesh K. Banavali and Alexander D. MacKerell, Jr. Protein-facilitated base flipping in DNA by cytosine-5-methyltransferase. PNAS, 2003, 100: 68-73.
44.	Yongping Pan, Niu Huang, Sam Cho and Alexander D. MacKerell, Jr. Consideration of Molecular Weight During Compound Selection in Virtual Target-Based Database Screening. J. Chem. Inf. Comput. Sci. 2003, 43: 267-272
45.	Niu Huang and Alexander D. MacKerell, Jr. An Ab Initio Quantum Mechanical Study of Hydrogen-Bonded Complexes of Biological Interest. J. Phys. Chem. A, 2002, 106: 7820-7827.
46.	Niu Huang, Linbo Qu, Qiqing Zhu, Fengming Chu, Guangzhong Yang and Zongru Guo. Studies on the Structure-Activity Relationship of Retinoids: Molecular Modeling of Interaction between Selective Retinoids Nuclear Receptors. Acta Pharmaceutica Sinica.1999, 34: 358-362
47.	Niu Huang, Fengmin Chu and Zongru Guo. Studies on the Structure-Activity Relationship of Retinoids: Hansch Analysis and 3D-QSAR Studies on Specific Ligands of Retinoid X Receptor. Acta Pharmaceutica Sinica. 1998, 33: 442-448
48.	Qiqin Zhu, Zongru Guo, Niu Huang, Minmin Wang, and Fengming Chu. Comparative Molecular Field Analysis of a Series of Taxol Analogues. J. Med. Chem, 1997, 40: 4319-4328
49.	Minmin Wang, Niu Huang, Guangzhong Yang and Zongru Guo. Studies on the Structure-Activity Relationship of Retinoids: II. 3D-QSAR of Retinoids and Receptor Interaction. Acta Pharmaceutical Sinica. 1997, 32: 43-48
50.	Niu Huang, Minmin Wang, Fengmin Chu and Zongru Guo. Studies on the Structure-Activity Relationship of Retinoids: I. 3D-QSAR of Retinoidal Anti-Carcinogenic Activities. Acta Pharmaceutica Sinica. 1996, 31: 932-939

1994	南开大学物理系生物物理学学士学位
	Bachelor of Biophysics，Department of Physics University of Nankai, Tianjin,
2003	马里兰大学巴尔的摩分校药学博士学位
	Ph.D.，Department of Pharmaceutical Sciences，University ofMaryland at Baltimore

2013年	北京生命科学研究所高级研究员
	Associate Investigator, National Institute of Biological Sciences, Beijing, China
2007-2012年	北京生命科学研究所研究员
	Assistant Investigator, National Institute of Biological Sciences, Beijing, China
2003-2007年	加利福尼亚大学旧金山分校药物化学系和生物医药学系博士后
	Postdoctoral associate, Depts. of Pharmaceutical Chemistry and Biopharmaceutical Sciences, University of California at San Francisco
1994-1998年	中国医学科学院&中国协和医科大学药物研究所研究助理
	Research assistant, Institute of Materia Medica, Peking Union of Medical College & Chinese Academy of Medical Sciences