本人致力于运用化学、计算、生物信息学等交叉学科方法，围绕计算机辅助药物设计（CADD）开发可以广泛使用的计算模拟方法和软件，解决CADD中的技术难点，提高药物筛选、设计的效率和准确性，扩展CADD在药物研发中的应用。同时围绕靶标蛋白的结构优化、功能性构象变化、靶标蛋白-药物的结合和相互作用进行基础性的机制和应用研究。

 

1. 药物靶标蛋白结构精修的计算模拟方法发展及应用

  基于结构的药物设计中，分子对接可以用来确定靶标蛋白中小分子结合的最佳位置和取向，在虚拟筛选中通过对结合构象打分排序，选择出最有可能与靶标结合的小分子。这一方法的成功依赖于靶标蛋白的结构精确性。在蛋白质数据库（PDB）中，很多靶标蛋白质的分辨率不高，尤其是位于结合口袋的loop区域缺失（由于其结构柔性很难被实验捕捉），此外很多的靶标蛋白的结构到目前仍未能确定。通常来说，可以用同源模建的方法来修补蛋白的缺失结构甚至从无到有地搭建蛋白的整体三维结构，然而通过同源模建搭建的结构准确性存在着很大的疑问。分子动力学模拟可用来对同源模建的结构进行精修以获得蛋白的最优稳定结构，但其耗费的计算资源和计算机时巨大。我们开发高效的分子模拟方法，从低分辨率的实验结构或模建结构出发，可以快速扫描获得靶标蛋白的优化结构，用于先导化合物的虚拟筛选，提高药物筛选的准确性。这一方法已被用于肿瘤相关靶点的B-RAF激酶的结构优化及构象变化机制研究。

 

2. 靶标蛋白的功能性构象变化及其对结合位点影响的新方法研究

  蛋白质发挥生物功能时通常伴随着大幅度的构象变化，构象间的变化既可能导致原有的药物结合位点形状及性质的变化，也有可能形成新的结合位点。这类动态运动很难通过实验手段检测。我们发展了多个增强取样的分子模拟方法，包括：正则模式分析-伞状取样分子模拟方法（NUMD）、混合显性/隐形水模型复本交换分子模拟方法（hREMD）、分配型温度积分取样分子动力学模拟方法（P-ITS)以及高斯偏执加速动力学方法（GbAMD）等。实现在原子层面上对靶标蛋白的大规模构象变化的快速、精确模拟，揭示靶标蛋白的功能运行机制，特别是：为药物筛选提供所有相关的功能性构象，因此可以在药物设计中充分考虑靶标蛋白的结构柔性，提高计算机辅助药物设计的准确率。研究的体系包括：EGFR蛋白、膜转运蛋白P-gp、免疫调节因子STING蛋白、B-RAF激酶、免疫缺陷病毒相关的HIV-1蛋白酶、钙调蛋白、GPCR蛋白CXCR1、蛋白质-RNA复合物等等。

 

3. 靶标蛋白-药物分子动态结合路径的确定以及潜在结合位点的预测新方法研究

  小分子（包括内源性的配体和外源性的药物分子）与靶标蛋白的结合遵循特定的路径进行。对药物分子的整个动态结合过程以及完整路径的研究可以提供多个重要的信息：

1）可以确定在药物结合中起重要作用的氨基酸残基，并以此为依据进行定向突变以改变靶标蛋白的可药性；

2）可以了解药物分子的结合机制以及结合动力学、热力学的影响因素，并在此基础上有针对性地进行药物分子结构的改造，改进药物的活性；

3）对潜在结合位点进行预测。

  我们发展增强取样分子模拟方法，可以在较短的计算模拟时间内给出药物分子与靶标蛋白动态结合的全局性信息。目前已实现了对多个靶标蛋白-药物体系（如胰蛋白酶-苯甲脒、HIV-1蛋白酶-DRV等）的动态结合路径研究，预期在将来可以大规模地应用于不同体系的药物分子改造和结合位点预测的研究。

 

4. 靶标蛋白-药物分子结合亲和力的计算方法发展及应用

  靶标蛋白-药物分子结合亲和力（binding affinity）在CADD中是一项评估药物分子活性的重要指标。但计算所得的结合亲和力很多时候与实验数值不一致，因此难以进行定量的评估。我们发展了蛋白质、小分子的可极化电荷力场参数QMPC, 可以显著提高蛋白质-药物分子结合亲和力的计算精确度。另一方面，发展增强取样分子模拟方法，最大程度地增加对结合口袋中小分子构象的扫描，定量地确定小分子结合的最佳构象。两者结合，为药物虚拟筛选提供更有效的工具。

 

5．复杂生物体系化学反应研究

  生物体系中的复杂反应（如酶催化反应）很难用实验手段进行研究，利用量子化学方法可以直接确定反应涉及的过渡态、中间体的结构和能量，从而对反应机制提供分子层面上的理解。本人使用目前生物体系反应机理研究中最为实用的分子力学/量子力学（QM/MM）混合方法对酶催化反应进行理论研究。

   

100720-药物设计学
070320-计算机化学

2004-08--2009-12 TexasA&M University, Texas, USA 博士
2003-08--2004-05 College of William & Mary, Virginia, USA 硕士
1999-09--2003-06 南京大学化学与化工学院 研究生毕业
1995-09--1999-06 南京大学化学与化工学院 学士

   

2020-10~现在, 中科院上海药物研究所, 研究员
2011-10~2020-10,中科院上海药物研究所, 副研究员
2010-01~2011-09,北京大学化学与分子工程学院, 博士后

2022年

1. Muya Xiong¹, Tianqing Nie¹, Qiang Shao, Minjun Li, Haixia Su, Yechun Xu^*. In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease, Eur. J. Med. Chem. 2022, 231：114130.  

2. Hangchen Hu, Qian Wang, Haixia Su, Qiang Shao, Wenfeng Zhao, Guofeng Chen, Minjun Li^*, Yechun Xu^*. Identification of Cysteine 270 as a Novel Site for Allosteric Modulators of SARS-CoV-2 Papain-Like Protease, Angew. Chem. Int. Ed. Engl. 2022, 61: e202212378.

2021年

1. Su, Haixia¹; Yao, Sheng¹; Zhao, Wenfeng¹; Zhang, Yuming¹; Liu, Jia¹; Shao, Qiang¹; Wang, Qingxing; Li, Minjun; Xie, Hang; Shang, Weijuan; Ke, Changqiang; Feng, Lu; Jiang, Xiangrui; Shen, Jingshan;Xiao, Gengfu; Jiang, Hualiang; Zhang, Leike*; Ye, Yang*; Xu,Yechun*. Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease, Nat. Commun. 2021, 12：3623.  

2. Xiong, Muya; Su, Haixia; Zhao, Wenfeng; Xie, Hang; Shao, Qiang^*; Xu, Yechun^*. What coronavirus3C‐like protease tellsus: From structure, substrate selectivity, to inhibitor design, Med. Res. Rev. 2021,41：1965-1998. 

3. Hui Zhang¹, Kun Chen¹, Qiuxiang Tan¹, Qiang Shao¹, Shuo Han¹, Chenhui Zhang, Cuiying Yi, Xiaojing Chu, Ya Zhu*, Yechun Xu^*, Qiang Zhao^*, Beili Wu^*. Structural basis for chemokine recognition and receptor activation of chemokine receptor CCR5. Nat. Commun. 2021, 12: 4151. 

2019年

1. Qiang Shao*, Weiliang Zhu. Ligand binding effects on the activation of EGFR extracellular domain. Phys. Chem. Chem. Phys. 2019, 21, 8141-8151. (*通讯作者)

2. Qiang Shao*, Weiliang Zhu. Nonnative Contact Effects in Protein Folding. Phys. Chem. Chem. Phys. 2019, 21, 11924-11936.

3. Qiang Shao*, Weiliang Zhu. Selective enhanced sampling in dihedral energy facilitates overcoming the dihedral energy increase in protein folding and accelerates the searching for protein native structure. Phys. Chem. Chem. Phys. 2019, 21, 10423-10435.

4. Qiang Shao*, Weiliang Zhu. Exploring the Ligand Binding/Unbinding Pathway by Selectively Enhanced Sampling of Ligand in a Protein−Ligand Complex. J. Phys. Chem. B 2019, 123, 7974-7983.

2018年

1. Qiang Shao*, Weiliang Zhu. Assessing AMBER force fields for protein folding in an implicit solvent. Phys. Chem. Chem. Phys. 2018, 20, 7206-7216. 

2. Qiang Shao*, Weiliang Zhu. The effects of implicit modeling of nonpolar solvation on protein folding simulation. Phys. Chem. Chem. Phys. 2018, DOI: 10.1039/C8CP03156H.

2017年

1. Qiang Shao*, Weiliang Zhu. Effective conformational sampling in explicit solvent with Gaussian biased accelerated molecular dynamics. J. Chem. Theory Comput. 2017, 13: 4240-4252.

2. Qiang Shao*, Weiliang Zhu. How well can implicit solvent simulations explore folding pathways? A quantitative analysis of α-helix bundle proteins. J. Chem. Theory Comput. 2017, 13: 6177-6190.

3. Qiang Shao*, Jiye Shi*, Weiliang Zhu. Determining protein folding pathway and associated energetics through partitioned integrated-tempering-sampling simulation. J. Chem. Theory Comput. 2017, 13: 1229-1243.

4.  Qiang Shao*, Zhijian Xu, Jinan Wang, Jiye Shi*, Weiliang Zhu. Energetics and structural characterization of the ‘‘DFG-flip’’ conformational transition of B-RAF kinase: A SITS molecular dynamics study. Phys. Chem. Chem. Phys. 2017, 19: 1257-1267.

5. Yuqi Yu, Jinan Wang, Zhaoqiang Chen, Guimin Wang, Qiang Shao*, Jiye Shi*, Weiliang Zhu*. Structural insights into HIV-1 protease flap opening processes and key intermediates. RSC Adv. 2017, 7: 45121-45128.

2016年

1. Qiang Shao*. Enhanced conformational sampling technique provides an energy landscape view of large-scale protein conformational transitions. Phys. Chem. Chem. Phys. 2016, 18: 29170-29182.

2. Yuqi Yu, Jinan Wang, Qiang Shao*, Jiye Shi*, Weiliang Zhu*. The effects of organic solvents on the folding pathway and associated thermodynamics of proteins: A microscopic view. Sci. Rep. 2016, 6: 19500.

3. Jinan Wang, Qiang Shao*, Benjamin Crossins, Jiye Shi*, Kaixian Chen, Weiliang Zhu*. Thermodynamics calculation of protein-ligand interactions by QM/MM polarizable charge parameters. J. Biomol. Struct. Dyn. 2016, 34: 163.

4. Jing Li1, Jose Pindado Rodriguez1, Fengfeng Niu, Mengchen Pu, Jinan Wang, Li-Wei Hung, Qiang Shao, Yanping Zhu, Wei Ding, Yanqing Liu, Yurong Da, Zhi Yao, Jie Yang, Yongfang Zhao, Gong-Hong Wei, Genhong Cheng, Zhi-Jie Liu, Songying Ouyang*. Structural basis for DNA recognition by STAT6. Proc. Natl. Acad. Sci. USA 2016, 113: 13015-13020.

5. Zhaoqiang Chen，Guimin Wang, Zhijian Xu*, Jinan Wang, Yuqi Yu, Tingting Cai, Qiang Shao, Jiye Shi*, Weiliang Zhu*. How do distance and solvent affect halogen bonding involving negatively charged donors? J. Phys. Chem. B 2016, 120: 8784-8793.

2015年

1. Yang Lijiang, Liu Chengwen, Shao Qiang, Zhang Jun, Gao Yi Qin*. From thermodynamics to kinetics: enhanced sampling of rare events. Acc. Chem. Res. 2015, 48:947-955
2. Yu Yuqi, Wang Jinan, Shao Qiang*, Shi Jiye*, Zhu Weiliang*. Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir. Sci. Rep. 2015, 5:10517.
3. Yu Yuqi, Wang Jinan, Shao Qiang*, Shi Jiye*, Zhu Weiliang*. Increasing the sampling efficiency of protein conformational transition using velocity-scaling optimized hybrid explicit/implicit solvent REMD simulation. J. Chem. Phys. 2015, 142, 125105.
4. Wang Jinan, Shao Qiang*, Crossins Benjamin, Shi Jiye*, Chen Kaixian, Zhu Weiliang*. Thermodynamics calculation of protein-ligand interactions by QM/MM polarizable charge parameters. J. Biomol. Struct. Dyn.2015, accepted
5. Shao Qiang*. Folding or misfolding: The choice of β‑hairpin. J. Phys. Chem. B 2015, 119:3893-3900.
6. Shao Qiang*. Important roles of hydrophobic interactions in folding and charge interactions in misfolding of α-helix bundle protein. ASC Adv. 2015, 5, 4191-4199.
7. Xiong Xiuming, Chen Zhaoqiang, Cossins Benjamin, Xu Zhijian, Shao Qiang, Ding K., Zhu Weiliang*, Shi Jiye*. Force fields and scoring functions for carbohydrate simulation. Carbohydr. Res. 2015, 401:73-81.

2014年
1. Wang Jinan, Shao Qiang*, Xu Zhijian, Liu Yingtao, Yang Zhuo, Cossins Benjamin, Jiang Hualiang, Chen Kaixian, Shi Jiye*, Zhu Weiliang*. Exploring transition pathway and free energy profile of large-scale protein conformational change by combining normal mode analysis and umbrella sampling molecular dynamics. J. Phys. Chem. B 2014, 118: 134-143.
2. Wang Jinan, Peng Shaoliang, Cossins Benjamin, Liao Xiangke, Chen Kaixian, Shao Qiang*, Zhu X*, Shi Jiye*, Zhu Weiliang. Mapping central α-helix linker mediated conformational transition pathway of calmodulin via simple computational approach. J. Phys. Chem. B 2014, 118, 9677-9685.
3. Shao Qiang*, Wang Jinan, Zhu Weiliang. On the influence of the mixture of denaturants on protein structure stability: A molecular dynamics study.  Chem. Phys. 2014, 441, 38-46.
4. Shao Qiang*. Probing sequence dependence of folding pathway of α-helix bundle proteins through free energy landscape analysis. J. Phys. Chem. B 2014, 118: 5891-5900.
5.Shao Qiang*. Methanol concentration dependent protein denaturing ability of guanidinium/methanol mixed solution. J. Phys. Chem. B 2014, 118: 6175-6185.
6.Shao Qiang*. The addition of 2,2,2-trifluoroethanol prevents the aggregation of guanidinium around protein and impairs its denaturation ability: A molecular dynamics simulation study. Proteins,2014, 82: 944-953.

2013年
1. Shao Qiang*, Wang Jinan, Shi Jiye, Zhu Weiliang. The universality of β-hairpin misfolding indicated by molecular dynamics simulations. J. Chem. Phys. 2013, 139: 165103/1-165103/8.
2. Shao Qiang*, Shi Jiye*, Zhu Weiliang. Molecular dynamics simulation indicating cold denaturation of β-hairpins. J. Chem. Phys. 2013, 138: 085102/1-085102/10.
3. Zhang Zhengyan, Xu Zhijian, Yang Zhuo, Liu Yingtao, Wang Jinan, Shao Qiang, Li Shujin, Lu Yunxiang, Zhu Weiliang.* The stabilization effect of dielectric constant and acidic amino acids on arginine-arginine (Arg-Arg) pairings: Database survey and computational studies. J. Phys. Chem. B, 2013, 117: 4827-4835. 
4.  Wu Tianmin, Yang Lijiang, Zhang Ruiting, Shao Qiang, Zhuang Wei.* Modeling the thermal unfolding 2DIR spectra of a β-hairpin peptide based on the implicit solvent MD simulation.  J. Phys. Chem. A, 2013, 117: 6256-6263.
5. Shao Qiang*. On the influence of hydrated imidazolium-based ionic liquid on protein structure stability: A molecular dynamics simulation study. J. Chem. Phys. 2013, 139: 115102/1-115102/8.
6. Wang Jinan, Fulford Tim, Shao Qiang, Javelle Arnaud, Yang Huaiyu, Zhu Weiliang,* Merrick Mike.* Ammonium transport proteins with changes in one of the conserved pore histidines have different performance in ammonia and methylamine conduction. Plos One 2013, 8: e62745. 

2012年
1. Shao Qiang, Zhu Weiliang, Gao Yi Qin.* Robustness in protein folding revealed by thermodynamics calculation. J. Phys. Chem. B 2012, 116: 13848-13856.
2. Shao Qiang*, Shi Jiye, Zhu Weiliang.* Enhanced sampling molecular dynamics simulation captures experimentally suggested intermediate and unfolded states in the folding pathway of Trp-cage miniprotein. J. Chem. Phys. 2012, 137: 125013/1-125013/10.
3. Shao Qiang*, Gao Yi Qin.* Water plays an important role in osmolyte-induced hairpin structure change: A molecular dynamics simulation study. J. Chem. Phys. 2012, 137: 145101/1-145101/10.
4. Shao Qiang, Fan Yubo, Yang Lijiang, Gao Yi Qin.* Counterion effects on the denaturing activity of guanidinium cation to protein. J. Chem. Theory Comput. 2012, 8: 4364-4373.
5. Shao Qiang, Fan Yubo, Yang Lijiang, Gao Yi Qin.* From protein denaturant to protectant: Comparative molecular dynamics study of alcohol/protein interactions, J. Chem. Phys. 2012, 136, 115101/1-115101/9 (封面文章, research highlights).
6. Lyu Zhi-Xin, Shao Qiang, Gao Yi Qin,* Zhao Xin Sheng.* Direct observation of the uptake of outer membrane proteins by the periplasmic chaperone Skp, Plos One 2012, 7: e46068.
7. Shao Qiang, Gao Yi Qin.* The protein folding mechanism revealed by the folding free energy landscape analysis and denaturation simulations, Curr. Phys. Chem. 2012, 2: 33-44.
8. Yang Lijiang, Shao Qiang, Gao Yi Qin.* Enhanced sampling method in molecular simulations, Prog. Chem. 2012, 24: 1199-1213.

2011年
1. Shao Qiang, Yang Lijiang, Gao Yi Qin.* Structure change of β-hairpin induced by turn optimization: An enhanced sampling molecular dynamics simulation study,J. Chem. Phys. 2011, 135: 235104/1-235104/10.
 2.Shao Qiang, Gao Yi Qin.* The relative helix and hydrogen bond stability in the B domain of protein A as revealed by ITS MD simulation, J. Chem. Phys.2011, 135: 135102/1-135102/12.
3. Hwang Soyoun1, Shao Qiang1, Williams Howard, Hilty Christian,* Gao Yi Qin.* Methanol strengthens hydrogen bonds and weakens hydrophobic interactions in proteins-A combined molecular dynamics and NMR study, J. Phys. Chem. B2011, 115: 6653-6660. (1共同一作)
4. Chen Liuxi, Shao Qiang, Gao Yi Qin, Russell H. David.* A molecular dynamics and ion mobility spectrometry study of modelβ-hairpin peptide, Trpzip1, J. Phys. Chem. A 2011, 115: 4427-4435.

2010年
1. Shao Qiang, Gao Yi Qin.* Temperature dependence of hydrogen-bond stability in β-hairpin structures, J. Chem. Theory Comput. 2010, 6: 3750-3760.
2. Shao Qiang, Wei Haiyan, Gao Yi Qin.* Effects of turn stability and side-chain hydrophobicity on the folding of β-structures, J. Mol. Biol.2010, 402: 595-609.
3. Wei Haiyan, Shao Qiang, Gao Yi Qin.* The effects of side chain hydrophobicity on the denaturation of simple β-hairpins, Phys. Chem. Chem. Phys.2010, 12: 9292-9299.
4. Lund Liliya, Fan Yubo, Shao Qiang, Gao Yi Qin,* and Raushel M. Frank.* Carbamate transport in carbamoyl phosphate synthetase: A theoretical and experimental investigation, J. Am. Chem. Soc. 2010, 132: 3870-3878.

2006~2009年
1. Gao Yi Qin,* Shao Qiang The chemomechanical coupling mechanisms of kinesin and dynein, Proteins Energy Heat & Signal Flow 2009, Book chapter.
2. Fan Yubo, Lund Liliya, Shao Qiang, Gao Yi Qin,* and Raushel M. Frank.* A combined theoretical and experimental study of the ammonia tunnel in carbamoyl phosphate synthetase,J. Am. Chem. Soc. 2009, 131:10211-10219.
3. Shao Qiang, Yang Lijiang, Gao Yi Qin.* A test of implicit solvent models on the folding simulation of the GB1 peptide, J. Chem. Phys. 2009, 130:195104/1-195104/6.
4. Yang Lijiang, Shao Qiang, Gao Yi Qin.* Thermodynamics and folding pathways of trpzip2: An accelerated molecular dynamics simulation study, J. Phys. Chem. B 2009, 113: 803-808.
5.Yang Lijiang, Shao Qiang, Gao Yi Qin.* Comparison between integrated and parallel tempering methods in enhanced sampling simulations, J. Chem. Phys. 2009, 130:124111/1-124111/8.
6. Gao Yi Qin,* Yang Lijiang, Fan Yubo, Shao Qiang. Thermodynamics and kinetics simulations of multi-time-scale processes for complex systems, Int. Rev. Phys. Chem. 2008, 27: 201-227.
7. Shao Qiang, Gao Yi Qin.* Asymmetry in kinesin walking, Biochemistry2007, 46: 9098-9106.
8. Shao Qiang, Gao Yi Qin.* On the hand-over-hand mechanism of kinesin, Proc. Natl. Acad. Sci. USA 2006, 103: 8072-8077.

   

（ 1 ） 核糖体对新生肽链,蛋白质与蛋白质之间的相互反应对蛋白质的折叠影响的理论模拟研究, 主持, 国家级, 2011-01--2013-12
（ 2 ） 自组装的理论与模拟, 参与, 国家级, 2011-01--2014-12
（ 3 ） 蛋白质大规模构象变化的模拟方法发展及应用研究, 主持, 国家级, 2014-01--2017-12
（ 4 ） 蛋白质复合体和膜蛋白结构生物学中的新技术和新方法研究, 参与, 国家级, 2014-01--2018-12
（ 5 ） 重要G蛋白偶联受体的结构与功能研究及配体发现, 参与, 国家级, 2012-01--2016-12
（ 6 ） 膜蛋白的结构精修及功能性构象变化研究, 主持, 市地级, 2017-03--2019-03
（ 7 ） NSFC-广东联合基金（第二期）超级计算科学应用研究, 主持, 省级, 2016-02--2017-07
（ 8 ） 针对EBOV、MERS-CoV、ZIKV、DENV、CHIKV造成的五种新发突发外来疫病的宿主和相关媒介的生物防控技术与产品的研发, 参与, 国家级, 2017-01--2019-12
（ 9 ） 膜蛋白的结构精修及功能性构象变化研究, 主持, 市地级, 2017-06--2019-01
（ 10 ） ACE2重组蛋白和多肽的设计改造研究, 主持, 国家级, 2021-01--2024-12