案例研究_从头药物设计_CaseStudy_DeNovoDesign.pdf

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1、Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Case Study:de Novo Design MOE应用案例研究：从头药物设计 分子模拟、药物设计及化学信息学部 E-mail:|Tel:021-54975000 ext.802 康昱盛信息科技有限公司 http:/ Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE 背景介绍 B

2、ackground Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE 从头药物设计的一般流程从头药物设计的一般流程 Given Target Structure 从头药物设计是基于结构的药物设计(SBDD)的一种设计思路。它依赖于对于靶标三维结构的深入理解以及对于化合物合成知识的全面掌握。从头药物设计提供给药化学家一种强有力的工具：使用这种工具，药化学家可以先在计算机上进行药物的设计、模拟与验证，然后进行化学合成、生物学验证及结晶结构解析，从而高效而艺术地实现新药

3、发现。Identify Active Site Build Molecule in Active Site Evaluate potency,synthesizability,toxicity,bioavailability based on computing prediction and knowledge Synthesize designed molecule Biology evaluation Development Good Optimize Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operat

4、ing Env ironment M OE 应用实例 Application Case Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE 特效降糖药特效降糖药Alogliptin的发现的发现 一种特效二型糖尿病治疗药物 DPPIV抑制剂阿格列汀的发现 Feng,J.,Zhang,Z.,Wallace,M.B.,Stafford,J.a,Kaldor,S.W.,Kassel,D.B.,Navre,M.,et al.(2007).Discovery of alogli

5、ptin:a potent,selective,bioavailable,and efficacious inhibitor of dipeptidyl peptidase IV.Journal of medicinal chemistry,50(10),2297-300.doi:10.1021/jm070104l Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE II型糖尿病在全球现状型糖尿病在全球现状 全球目前有1亿8千万人口罹患II型糖尿病一种由于复杂因素引

6、起的胰岛素抗性和胰岛素分泌损伤 预计到2030，患病人口会增加一倍 开发有效的降糖药物成为各大制药公司追求的目标 Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE 故事的开始故事的开始 2006年，来自雅培(Abbott)的科学家发布了一个结晶结构：共价结合抑制剂cyanopyrrolidine与DPPIV酶复合物；这个结晶结构给了科学团体很多有益的启示 PDB ID:2G5T Pei Z.,et al.JMC.2006 Copyright 2013 CloudS

7、cientific All Rights Reserved.M olec ular Operating Env ironment M OE 如何基于如何基于DPPIV酶结构设计新抑制剂？酶结构设计新抑制剂？Hydrophobic Pocket Hydrogen Bonding Spot Ionic Bonding Spot 可以设计出满足这些相互作用的非共价抑制剂吗？Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE 如何基于如何基于DPPIV酶结构设计新抑制剂？酶

8、结构设计新抑制剂？Compound 1a Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part1:Structure Loading and Preparation 1.Open 2onc.pdb*from MOE|File|Open Enter the pdb code 2onc into the field,select the entry,then press OK.2.Load PDB File with default settings.*We u

9、se 2ONC,but not 2G5T,as the structure for de novo design,because it is the complex of lead compound of Alogliptin 1a and DPPIV.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part1:Structure Loading and Preparation 3.Keep only one chain and the inhibitor,de

10、lete all the others from the Sequence Editor.Select the chains you want to delete,right click the mouse,and choose Delete Click OK to confirm deletion Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part1:Structure Loading and Preparation 4.Delete the secon

11、d inhibitor.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part1:Structure Loading and Preparation 5.Keep the receptor atoms within 10 around the inhibitor,delete others.Select the inhibitor,MOE|Select|Atom Selector,set Radius to 10,click Proximity,then ex

12、tend to Residues.Finally,click Invert.3 1 2 RHS|Delete,confirm deletion.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part1:Structure Loading and Preparation 6.Add hydrogens to the system,MOE|Compute|Prepare|Protonate 3D.7.Fix the receptor atoms.Right cli

13、ck,Popup Menu|Select|Receptor,RHS|Constraint|Fix.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part1:Structure Loading and Preparation 8.Minimize the system:RHS|Minimize,then save the prepared file.Please be aware that the forcefield used for this case sh

14、ould be MMFF94x or AMBER12EHT.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part2:Design the DPPIV Inhibitor from Scratch 1.Use current inhibitor as reference,observe the structure and interaction with receptor.Then inactive and hide it.Select the ligand,

15、MOE|Edit|Potential|Inert.Right click,Popup Menu|Hide|Selected Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part2:Design the DPPIV Inhibitor from Scratch 2.The S1 pocket is a hydrophobic pocket,of which size is suitable for 5 or 6 member ring,lets use ben

16、zene to fit it.RHS|Builder Change the view of benzene(small molecule)to facilitate us to differ the ligand and receptor.Select the benzene,right click,Popup Menu|Atoms|Stick Mode Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part2:Design the DPPIV Inhibit

17、or from Scratch 3.Select the newly added benzene,rotate and drag it into the S1 pocket,then minimize to make it to find a comfortable pose.Double Click the atom on benzene to select the benzene Alt+Middle Key to rotate Shift+Alt+Middle Key to move RHS|Minimize to minimize the system Tips:You may try

18、 several time that rotate+drag+minimize to make sure that there is a good place for benzene in S1 pocket.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part2:Design the DPPIV Inhibitor from Scratch 4.Add-CN to benzene to form hydrogen bond with Arg125,then

19、 minimize.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part2:Design the DPPIV Inhibitor from Scratch 4.Add CH3 to benzene to make an extension point,then minimize.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE

20、Part2:Design the DPPIV Inhibitor from Scratch 5.Add quinazolinone to CH3 to form hydrogen bond with Tyr631.Tips:you may move the new molecule several times and minimize to find a good place for it.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part2:Design

21、 the DPPIV Inhibitor from Scratch 5.Add aminopiperidine to C-2 of quinazolinone to make salt bridge with Glu205/206.Tips:-NH3 group at C-3 of piperidine adopted the R configuration.And the conformation of piperidine(two different boat conformations)will affect the results.Copyright 2013 CloudScienti

22、fic All Rights Reserved.M olec ular Operating Env ironment M OE Part3:The strain energy and ring conformation During the design process,you may watch the strain energy of the new molecule.The strain energy can be calculated with RHS|Ligand|Ligand Propterties,or with the customized module develeoped

23、by CloudScientific(RHS|Ligand Strain).*The strain energy is the difference between the binding conformation and the nearby local minimum.This can be an indicator that how stable the ligand will stay at the binding site.Cyan:the nearby local minimum conformation Copyright 2013 CloudScientific All Rig

24、hts Reserved.M olec ular Operating Env ironment M OE Part3:The strain energy and ring conformation The strain energy is greater than 10 kcal/mol,which means it is unstable or there is another stable binding conformation exists.Because the piperdine is a 6-member saturation ring,so there is another s

25、table chair conformation.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part3:The strain energy and ring conformation Brown:the first design molecule;strain energy 13.58 kcal/mol Yellow:the one with anther chair conformation;strain energy 6.14 kcal/mol Gre

26、en:the crystal structure;strain energy 5.36 kcal/mol Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part3:The strain energy and ring conformation Almost all the designed features have been achieved.Go to synthesize and test it.Copyright 2013 CloudScientifi

27、c All Rights Reserved.M olec ular Operating Env ironment M OE Part4:Synthesize,test and optimize Alogliptin Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE Part4:Synthesize,test and optimize Alogliptin was approved and marketed in Japan in 2010,and approved

28、 by FDA in early 2013.Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE 总结总结 Summary 针对一个新的药物靶标，基于结构的药物设计往往从虚拟筛选开始，然而我们往往难以筛选到高效、高度选择性的先导化合物。从头药物设计提供了一种全新的基于结构药物设计思路和方法。基于对靶标结构和化合物结构知识的深入理解与掌握，我们有可能设计出结构新颖、高效的药物。事实上，掌握这种方法的使用并不困难。从头药物设计可以成为药化学家、有机合成专家、计算机辅助药物设计专家手头的利器。Copyright 2013 CloudScientific All Rights Reserved.M olec ular Operating Env ironment M OE 致谢致谢 Acknowledgement