近十多年来，利用计算机高速计算绘图软件包，从事学术研究或产业界先导性研发，已蔚为另一热门研究领域。此「趋势发生在制药工业尤其明显。主要原因是利用计算机辅助药物设计具有缩短研发时程，降低成本，提高药物品质等多项优点，恰能解决已往开发新药所遭遇的缺失。 药物分子产生药效前，多必需与目标蛋白质大分子，脢或受体，结合。结合部位多埋于蛋白质大分子结构深层内部，而结合部位空间正足以包容药物分子立体构形之体积。发生结合时所需的结合力则是藉由药物分子结构中的官能基团 ( Funclional Groups ) 与蛋白质结合部位胺基酸分子的官能基团二者间相互吸引所衍生的离子性键、拒水性力 ( HydroPhobic Force ) ，氢键与凡得瓦力等微弱分子间引力。计算机辅助药物设计的策略是植基于药物与目标蛋白质大分子的结合部位具有分子外形互补与携带电荷互补的理论基础上。它们二者间互补的关系正如锁和钥匙一般 计算机辅导药物设计的前题是先要有蛋白质大分子结构锁的资料，而锁结构物资料获得的方式有三 : (一) 由蛋白质晶体经过X射线绕射分析得。(二)溶解态的蛋白质利用 2D NMR技术获得。(三)利用模拟法 ( Homology)来建立相关蛋白质分子结构。三方式中，以第一种方式得到的结构资料最精确，唯晶体的养成与否是运用此法的先决条件。此外锁的结构亦可自现有资料中读取。目前蛋白质分子结构数据库中存有约 1400个鲒构资料可资运用。一旦锁的结构确定后，设计人员可按照其结构，经由人坞 ( Docking ) 或调适 ( FMing ) 尝试，设计体积符合活性部位的化合物分子，继之以修饰此化合物，例如改变化合物分子结构中极性基团，增加脂溶性基团，新增或去除键以改变分子立体构形，加入吸取或释放电子基团 ( Electron Withdrawing or Releasing Groups ) 以 改变分子中各原子电荷分布等方式以增加化合物分子与蛋白质活性部位结合时之吸引力。 计算机辅助药物设计实例中 ，Dihydro folate Re- duclase ( DHFR )脢抑制剂的药物设计是个极佳的范例。 图一是已知的抑制剂 Melholrexate ( MTX ) 与DHFR活性部位结合时之示意图。MTX分子中蝶啶(peridine)杂环上 1 位氮原子及2位胺基与脢活性部位第27位天『1冬胺酸的羧基形成电辅氢键 ( charge一Assisted Hydrogen Bonding ) 。 (二)MTX 分子中2一羧基与腌活性部位第57位精胺酸脉基离子 ( Guanidinium Group )形成之氢链。(三)MTX 分子中苯环与脢活性部位第28及50位之白胺酸及白胺酸所携带之拒水性基团形成拒水性力。当了解了 MTX与DHFR作用机制及DHFR活性部位胺酸位置，接下来设计新化合物的工作就方便许多。 TrimelhoPrim，一个化学结构与 MTX 类似的化合物，它分子体积经由人坞尝试恰能航人DHFR活性部位。它与 DHFR 结合时情形如图二所示。 TrimethoPrim与DHFR二者间所形成分子间引力有 (一)前者分子中呲啶环上1位氮原子及2位胺基与醣活性部位第27位天门冬胺酸的羧基形成电辅氢键。(二) 前者分子中苯羧与腌活性部位第28及50位白脸酸及异白脸酸所携带之拒水性基团形成拒水性力。当比较腌活性部位与MTX成TFimelhoPrim 所发生分子间引 力时发现， MTX 较 TFinelhoPrim 多了一个由 MTX分子中 alpha一羧基与醣第57位精胺酸脉基离子所形成之氢键结合力。如何修饰 trimelhoPrim分子方能增加它与腌活性部位二者间结合力(Birding Affinily ) 呢? 学者KuyPer 氏等人提出了设计的方向。方法是将trimethoPrim 分子中苯环上三个中氧 ( Melhoxy GrouP)取代基中的一个甲氧基修改成绞基，并以亚基甲 ( Methylene GrouP ) 为桥梁， 以增加亚甲基数目的方式，将末端羧基廷申至DHFR 醣57位精胺酸脉基邻近位置以利于形成分子间氢键。设计的新化合物经由有机化学人员合成后再交由生物化学人员来测试化合物与腌的亲和力。结果如表一 所示。以不同亚甲基数目为桥键的设计方式所得到的化合物能促使醣与化合物之结合力提高。其中桥键为 5个亚基的化合物，亲和力更高达原有的54偣。由以上设计实例可知，未来使用计算机仿真药物分子与腌结合时情形及用计算机辅助药物设计绝对能事半功偣，提高成功的机率。最近美国加州大学旧金山校区学者 Shoich， etal 氏等人于 1993 年 Science 期刊 259 卷 1445 页发表有关 Thymidylale Synlhase 及美国杜邦默克药品公司专家Lam 氏等人于 1994 年 Science 期刊 263 卷，380 页发表关于 HIV protease 等二种醣新型抑制剂。这些都是连用计算机科技从事新药设计成功的实例。 以上简介计算机辅助药物设计的方法，另外对于选择计算机硬件及软件包也有不同的考量。从经济效益角度来说，个人型工作站已足够满足简单计算的需求，复杂的计算，则可透过网络委由国家高速计算机中心的超级计算机来处理。至于软件包部分，有爱好的读者不妨参考由学者 Cohen 氏等人于 1990 年 J．Med．．Chen 期刊 33卷 883 页发表的回顾性专论中了解各不同软件包的功能。但是，有时仅仅参考介绍软件功能的书面资料，买者很难购买到最符合本身研究所需的软件。笔者建议，若能询问专家，譬如洽询国家高速计算机中心分子仿真小组成员，或者亲赴国家高速计算机中心分子仿真室实地上机操作各种软件包，必有助于买者选择到最符合本身研究需求的硬件、软件 在新药开发过程中，新药设计仅仅是第一线作业，接下来还须要经过后续的药物合成，药理及毒性筛选试验，临床试验等阶段以及最后的药物上市方才算是一个完整新药开发过程。由于国家高速计算机中心的成立及辖下分子仿真小组的推动，目前已凝聚了一批计算化学、分子仿真等专家学者。加以该中心已举行一连串计算化学，药物设计，分子仿真等研习会、研讨会，更推广了计算机科技于药物开发研究的运用。而上述这些汇聚、培育的人才，正可做为第一线药物设计的构思者。至于第二线的药物合成工作，由于国内合成化学界宿享有声誉，并且已储备了有机合成人才，可资用为新药合成的最佳人选。令人担忧的是药理及毒性试验，临床试验，国内目前似乎未对此方面有前瞻性的设计与规划。笔者以为国科会生物处或可考虑等设功能类似精密仪器中心般附属于大专院校的药理及毒性筛选中心。或是直接扩充已有基础之药理及毒性实验室，并以经费支持经常性人力、物力以专职处理各界委托药物之药理及毒性筛选事宜。此外，引进国外新药临床试验制度，制定相关法律规范等都是值得考虑进行的。 正值国家面临经济型态转型期，台湾经济能否再创高峰端赖国内高科技产业的发展能否提升。然而发展高科技产业并非一蹴可及，因此衷心期盼学界的领航者，国科会能责无旁贷负起整合与推动的责任，促成学术界与产业界携手合作，共同为国家工业产业升级努力。尤其是制药工业的产业升级则是我们从事药学研究的人员所最乐意见得的。 ( 作者现职于国防医学药学系 )
一步一步学计算机辅助药物设计（一）
1. 做生物大分子结构的pc机配置
转自biolover biohity的推荐配置
1. 二手主板Tyan(泰安) Tiger MPX S2466N-4M 加两个Athlon MP 2400+ (是用XP 1700+改装的）。总共3900元
2. 二手野猫4110显卡：$110.00 + ￥160关税。（未用上，因AGP口不配）。改用Synergy II显卡：250元
3. 二手DC390U3W的SCSI卡：800元
4. 36G日立全新硬盘：1100元
5. SGI 1600SW 原装、全新液晶monitor：$1200 ＋ ￥1500（关税）
6. 美基P4-450瓦电源：450元；月光机箱：350元
7. 内存 512M;
8. 系统：win2000及Linux（在不同的硬盘上）。RedHat 7.2。
SGI的机子也很轻易在国内买到极好的二手。O2-5K-200Mhz大约2100元即可买到。Octane-R12k-300Mhz则贵些。但ebay上只要$300～400即可。PC机是无法与这类机子相提并论的。要知道，1999年时，上述Octane要卖两万美元啊！
1、假如你在上海，进入易趣网站
www.eachnet.com，在电脑--%26gt;工作站或服务器的栏目下，找ninjaa这个人即可。
2、假如你在北京，
http://www.qianye.y365.com/newpage5.html 并电话联系即可，此人有Octane的各种机子卖，但要价太贵。
3、美国ebay上较便宜，但每台进口的Octane要交400元人民币左右的关税
2. 再看看相关的教材和期刊
(1)入门教材
biolover Alchemy推荐
Hyperchem里有一本书，叫“Computational Chemistry”，个人觉得比较经典。以前是独立出来的PDF，现在集成到27M/2700页的大个头里面了。
刘次全 编过一本“量子生物学”，随后编了“结构生物学”等，呵呵，神人
BioMedCAChe的UserGuide是比较通俗的
(2)推荐使用软件
Hyperchem，ICM，BioMedCAChe
(3)相关的部分专业期刊
转自biolover biotech_lqh发贴
DDT（drug discovery today)
http://www.drugdiscoverytoday.com/ PROTEINS-STRUCTURE FUNCTION AND GENETICS
http://journals.wiley.com/0887-3585/ BIOINFORMATICS
http://bioinformatics.oupjournals.org/ BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY
http://www.elsevier.com/locate/issn/01674838 JOURNAL OF MEDICINAL CHEMISTRY
http://pubs.acs.org/journals/jmcmar/index.html JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
http://www.kluweronline.com/issn/0920-654X/contents JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES
http://pubs.acs.org/journals/jcisd8/index.html JOURNAL OF MOLECULAR GRAPHICS %26 MODELLING
http://www.elsevier.nl/locate/inca/525012 JOURNAL OF BIOMOLECULAR STRUCTURE %26 DYNAMICS
http://www.jbsdonline.com/一步一步学计算机辅助药物设计
3. 还得熟悉一下有哪些大公司
开发分子模拟软件的一些公司及其网址
Tsar 、CAChe、Chem-X、UniChem、AMBER 、AMSOL 、AutoDock Oxford Molecular公司
http://www.oxmol.com/ Cerius2 、InsightII、WebLab、Catalyst、FELIX、QUANTA Molecular Simulations Inc. (MSI) 公司
http://www.msi.com/ SYBYL, CoMFA, Biopolymer, TRIAD, GeneFold, MOLCAD, Alchemy Tripos
公司
http://www.tripos.com/ ChemDraw, Chem3D,ChemFinder,CambridgeSoft (CS)公
http://www.camsoft.com/ Gaussian Gaussian, Inc. 公司
http://www.gaussian.com/ SPARTAN、TITAN Wavefunction, Inc公司
http://www.wavefun.com/ PCMODEL Serena Software公司
http://www.serenasoft.com/ MOPAC Fujitsu Ltd.公司
http://www.fujitsu.com/ Conformer Princeton Simulations公司
http://www.conformer.com/ 一步一步学计算机辅助药物设计
4. 开讲了，先讲讲分子对接，这里主要是指有机分子和受体的对接
受体当然是蛋白，有晶体结构的话，先学学PDB的格式(略)
蛋白结构模拟全攻略
1 先熟悉一下几个蛋白结构的数据库
Protein Structure Databases. Comparison and Classification of Protein Structures.
The study, comparison and classification of the already known protein structures allows to extract information about sequence/family/structure relationships that can be used latter for predictions.
PDB. The database of protein structures.
http://www.rcsb.org/ PDBsum. Summaries and structural analysis of PDB files.
http://www.biochem.ucl.ac.uk/bsm/pdbsum/ OCA. Integration of PDB with other sources of data.
http://oca.ebi.ac.uk/ SCOP. Human expert classification of protein structures.
http://scop.mrc-lmb.cam.ac.uk/scop/ FSSP(Dali). Automatic classification.
http://www.ebi.ac.uk/dali/ CATH. Semi-automatic classification.
http://www.biochem.ucl.ac.uk/bsm/cath_new/index.html 2 对于从来没做过结构的新手，可以看这里
The structure prediction Meta Server
http://bioinfo.pl/meta/ The structure prediction Meta Server offers a gateway to many high quality fold recognition servers and provides and infrastructure and main interface to several highly reliable consensus methods. The Meta Server represents the firs step in the our fold prediction strategy.
这是个大杂烩，是不是用了它其他的都不用了？ ；）
3 假如想多了解几个基于web的结构猜测网站，可以看看这些
Web-based Comparative Protein Modelling Resources
SwissModel
http://www.expasy.ch/swissmod/ SWISS-MODEL is an Automated Protein Modelling Server running at GlaxoSmithKline in Geneva (Switzerland) and the Advanced Biomedical Computing Center (NCI, Frederick MD).
CPHModels
http://www.cbs.dtu.dk/services/CPHmodels/ Protein structure prediction server using distance constraints.
Center for Biological Sequence Analysis. (The Technical University of Denmark, Denmark).
SDSC1
http://cl.sdsc.edu/hm.html San Diego Supercomputer Center Protein Structure Homology Modeling Server
3D-JIGSAW
http://www.bmm.icnet.uk/servers/3djigsaw/ 3D-JIGSAW is an automated system to build three-dimensional models for proteins based on homologues of known structure.
ESyPred3D
http://www.fundp.ac.be/urbm/bioinfo/esypred/ ESyPred3D is an Expert System for the Prediction of proteins 3D structures running at the University of Namur (Belgium). The specificity of ESyPred3D is the building of the target-template alignment by combining several alignment programs.
Pcomb-Pcons
http://www.sbc.su.se/~arne/pcomb/ Pcomb-Pcons uses a combination of several sequence-profile and profile-sequence searches. It produces both homology modelling models and alignments.
Web-based Threading Resources
3D-PSSM
http://www.sbg.bio.ic.ac.uk/~3dpssm/ Protein fold recognition using 1D and 3D sequence profiles coupled with secondary structure and solvation potential information.
FUGUE
http://www-cryst.bioc.cam.ac.uk/~fugue/ The program FUGUE searches a sequence or sequence alignment against the library of profiles. Environment-specific substitution tables were derived from the structure-based alignments in the HOMSTRAD database. Each alignment in HOMSTRAD was converted into a scoring template (profile) using the environment-specific substitution tables and environment-dependent gap penalties.
123
http://123d.ncifcrf.gov/ Libellula
http://www.pdg.cnb.uam.es:8081/libellula.html SAMt99
http://www.cse.ucsc.edu/research/compbio/HMM-apps/model-library-search.html SAUSAGE
http://rsc.anu.edu.au/~arussell/TheSausageMachine.html Sausage (Sequence-structure Alignment Using a Statistical Approach Guided by Experiment) is a protein threading program.
Superfamily
http://supfam.mrc-lmb.cam.ac.uk/SUPERFAMILY/index.html Protein domain assignments to SCOP structural superfamilies using a hidden Markov model library.
bioinbgu
http://www.cs.bgu.ac.il/~bioinbgu/form.html 4 假如想看看猜测后的结果，可以用一下Swiss-PdbViewer
同源模拟之swiss-model
SWISS-MODEL
http://www.expasy.org/swissmod/SWISS-MODEL.html SWISS-MODEL is a fully automated protein structure homology-modeling server, accessible via the ExPASy web server, or from the program DeepView (Swiss Pdb-Viewer). The purpose of this server is to make Protein Modelling accessible to all biochemists and molecular biologists World Wide.
Swiss-PdbViewer
http://www.expasy.org/spdbv/mainpage.htm a tool for viewing and manipulating protein structures and models (Macintosh, PC, SGI and Linux).
非常轻易上手，适合初学者使用，有具体的说明，以及邮件列表可以咨询
5 假如觉得想自己动手，模拟一个，可以试试modeller
同源模拟之modeller
MODELLER
据说是目前最好的同源模拟软件
http://salilab.org/modeller/ MODELLER is used for homology or comparative modeling of protein three-dimensional structures (1). The user provides an alignment of a sequence to be modeled with known related structures and MODELLER automatically calculates a model containing all non-hydrogen atoms. MODELLER implements comparative protein structure modeling by satisfaction of spatial restraints (2, 3), and can perform many additional tasks, including de novo modeling of loops in protein structures, optimization of various models of protein structure with respect to a flexibly defined objective function, multiple alignment of protein sequences and/or structures, clustering, searching of sequence databases, comparison of protein structures, etc. MODELLER is written in Fortran 90 and runs on the Pentium PC%26#39;s (Linux and Win XP), Apple Macintosh (OS X) and workstations from Silicon Graphics (IRIX), Sun (Solaris), IBM (AIX), and DEC Alpha (OSF/1).
6 模拟完得评价一下,不过这有些难度,我是没搞懂,请哪位大侠指点指点
Model Evaluation.
Once a model has been generated, these tools allow to evaluate its quality.
EVA
http://maple.bioc.columbia.edu/eva/ EVA continously and automatically analyses protein structure prediction servers in %26#39;real time%26#39; Columbia %26 Rockefeller Univ, New York.
Biotech Validation Suite.
http://biotech.embl-heidelberg.de:8400/ Based on the tools implemented in the WhatIf program.
WhatCheck / WhatIf Gert
http://www.cmbi.kun.nl/whatif// ProSA II.
http://www.came.sbg.ac.at/Services/prosa.html 5. 接着如何取得有机小分子的配体呢，请看
biolover上这样说
问：谁知道怎么搭小分子配体的结构,然后再和蛋白做docking? 是有现成的立体结构库可用,还是手工搭建?
答：一般是ISIS draw画出已知结构，Hyperchem等优化，找搞化学的人问问
ISIS/Draw
ISIS/Draw
http://www.mdli.com/ 免费的画小分子结构的软件
一个简单介绍
http://www.ch.cam.ac.uk/SGTL/MDL/ISISdraw.html 其实网有免费2D转3D的软件CORINA
http://www2.chemie.uni-erlangen.de/software/corina/index.html 它需要输入SMILES格式
http://www.daylight.com/dayhtml/smiles/ 还可以看看以下的帖子
如何寻求化合物信息
Chemfinder
http://chemfinder.cambridgesoft.com/ 有机所的数据库
中药与有效成分数据库,药物与天然产物数据库等等
http://202.127.145.69/database/sjk.htm 还有两个大公司的产品目录也不错
Sigma
http://www.sigmaaldrich.com/ Acros
http://www.acros.be/ 还能得到一些化合物的3D结构
中国天然产物数据库（CNPD）
中国天然产物数据库
http://www.neotrident.com/neotrident_def4_1.htm CNPD数据库包括两方面内容, 一是库治理系统, 二是数据本身。
1. CNPD的数据库是利用MDL公司先进的化学信息治理系统ISIS/Base %26 Draw进行治理应用的。 使用者无需任何专业计算机知识, 不需学习任何编程语言, 即可利用ISIS/Base %26 Draw对CNPD数据库自如地进行检索、浏览、维护。
使用者在使用ISIS/Base %26 Draw对CNPD数据库进行检索时, 还可以使用到一种非常有效并诱人的新功能--结构式搜寻。 化学结构式是化学家的通用语言, 当化学家利用结构式搜寻功能对CNPD数据库进行检索时, 可以非常准确的得到他们所需的信息。
Windows 环境下运行的数据库治理软件ISIS/Base%26Draw, 使CNPD易于把握使用。
2. CNPD 目前共收集了2000余条中国天然产物的化学结构及性质信息, 主要包括以下几类天然产物:
生物碱 / 萜类 / 甾体类 / 皂苷类 / 鞣
黄酮类 / 香豆类 / 蒽醌类 / 木酚素类 / 类酯
CNPD收集的中国现有的天然产物的信息, 主要包括以下几个方面内容:
?天然产物的二维分子结构及利用分子力学方法优化得到的三维分子结构。三维分子结构与生物活性资料相结合, 可探索分子结构和活性间的相互关系。
?天然产物的名称、分子式、分子量、熔点、旋光度等重要物理性质。
?天然产物的CAS登录号, 为方便地关联其它化学信息资源提供了便捷的接口。
?一些天然产物的生物活性信息。
?天然产物的植物来源。
?原植物在中国传统医药中的应用。通过与其它信息相关联, 可导出一些新的信息。
?参考文献。(包括文献来源、作者、年代等具体信息)
CNPD的应用
CNPD可以对从事天然产物、 有机化学、 医药、 农药、 植物化学及生物化学等领域的研究员提供有益的帮助, 如:
?可以系统的了解天然产物分离、提取和鉴定的研究方法。
?可以对天然产物的结构及生物活性信息进行定量或定性的分析研究, 以深入了解某类药物的结构与活性间的关系, 为新药研究提供系统的和有价值的信息。
?由于天然产物的结构具有非常好的差异性, 因此天然产物数据库可以作为一个非常有效地组合化学化合物数据库的数据源。
?CNPD让你充分了解中国天然产物资源
→首次将天然产物、生物活性数据、原植物来源及中药传统应用融合在一起。
→三维结构信息及其在线显示。
CNPD的升级/补充
中国的科学家在对天然产物及中草药研究中积累了大量的信息资料, CNPD将通过每年的版本升级来充实完善数据库, 包括新条目的补充以及条目内容的增加等。
最低系统基本要求:
?IBM微机或100%兼容机；
?80486或更高微处理器；
?VGA或更好显示器
?微软Windows兼容鼠标
?微软Windows 95/98/2000/NT
?8MB以上内存
?硬盘空间: ISIS/Draw 15MB； ISIS/Base 40 MB； CNPD 6MB以上
CNPD DEMO CD CONTENT
?500 compounds in all, including:
?Alkaloids (生物碱) 75
?Carbohydrates (碳水化合物) 11
?Coumarins (香豆素) 36
?Flavonoids (黄酮类似物) 40
?Terpenoids (萜类) 75
?Steroids (类固醇) 40
?Lignans (木脂素类) 61
?Anthraquinone (蒽醌) 37
?Phenols (苯酚) 58
?Polyacetylenes (多炔) 19
?Saponins (皂角苷) 40
?Lactones (内酯) 3
?Esters (酯) 5
----------------------------------------------------------------
demo光盘可以要到，找负责化学信息学的陈利先生，他很热心的，只可惜数据要用ISIS/base才能打开看
Dock screening Database
分子結構資料庫：這些資料庫都可做2D、3D結構和文數字搜尋
acdfind.db：化合物商業來源資料庫
mddr3d.db︰藥用化合物資料庫
cmc3d.db：藥用化合物資料庫
nci3d.db：美國癌症研究院分子結構資料庫
nciaids.db：美國癌症研究院抗癌和抗愛滋病分子結構資料庫
csd2d.db：英國劍橋晶體結構資料庫
isismx.db：學習用分子結構資料庫
不知道哪位能知道以上数据库的下载地址
一步一步学计算机辅助药物设计
6. 要格式转化，请看
babel 是一个很好的格式转化软件
http://www.ccl.net/cca/software/SOURCES/C/babel/index.shtml The Dundee PRODRG Server 也不错
http://davapc1.bioch.dundee.ac.uk/prodrg7. 开始介绍分子对接软件
分子对接（docking）相关软件
QXP(Flo+)
http://uwmml.pharmacy.wisc.edu/Flo/floindx.html 据说是最牛的，牛软件是没有介绍的，它是Flo program中的一部分，可以下载，但有密码，不知道有没有人能down下来
Glide
http://www.schrodinger.com/Products/glide.html Glide is a fast and accurate docking program that addresses a number of problems, ranging from fast database screening to highly accurate docking. Binding mode studies show a remarkable accuracy of 1.3 ? average RMS deviation relative to co-crystallized drug-sized structures in the Gold test set. In database screening, Glide performs consistently well over a wide range of receptor types, with enrichment factors of 53 for Estrogen Receptor and 66 for Sugar-Binding Protein.
评价不错的软件
dock
http://www.cmpharm.ucsf.edu/kuntz/ DOCK addresses the problem of %26quot;docking%26quot; molecules to each other. It explores ways in which two molecules, such as a drug and an enzyme or protein receptor, might fit together. Compounds which dock to each other well, like pieces of a three-dimensional jigsaw puzzle, have the potential to bind. So, why is it important to able to identify small molecules which may bind to a target macromolecule? A compound which binds to a biological macromolecule may inhibit its function, and thus act as a drug.
DOCK generates many possible orientations (and more recently, conformations) of a putative ligand within a user-selected region of a receptor structure. These orientations may be scored using several schemes designed to measure steric and/or chemical complementarity of the receptor-ligand complex. These scores may be used to evaluate likely orientations of a single ligand, or to rank molecules from a database.
这可是分子对接软件的鼻祖，不过已经不是最好的了
Autodock
http://www.scripps.edu/pub/olson-web/doc/autodock/ AutoDock is a suite of automated docking tools. It is designed to predict how small molecules, such as substrates or drug candidates, bind to a receptor of known 3D structure.
It has applications in:
X-ray crystallography;
structure-based drug design;
lead optimization;
virtual screening (HTS)
combinatorial library design
protein-protein docking
chemical mechanism studies
AutoDock actually consists of three separate programs: AutoDock performs the docking of the ligand to a set of grids describing the target protein; AutoGrid pre-calculates these grids; and AutoTors sets up which bonds will treated as rotatable in the ligand.
In addition to docking, the atomic affinity grids can be visualised. This can help , for example, to guide organic synthetic chemists design better binders.
We have also developed a GUI called AutoDockTools, or ADT for short, which helps to set up and analyze dockings. We have an automated packager to help you download all the parts of ADT.
GOLD
http://www.ccdc.cam.ac.uk/prods/gold/index.html GOLD is a program for predicting how flexible molecules will bind to proteins - a problem of enormous significance in the rational design of drugs and combinatorial libraries.
GOLD Features:
a genetic algorithm methodology for protein-ligand docking
full ligand and partial protein flexibility
energy functions partly based on conformation and non-bonded contact information from the CSD.
Choice of scoring functions in version 2.0: GoldScore and ChemScore
A range of constraints
可免费试用
FlexX
FlexX
http://cartan.gmd.de/flexx/ FlexX WWW Interface
http://cartan.gmd.de/flexx//html/flexx-interface.shtml FlexX is a computer program for predicting protein-ligand interactions. For a protein with known three-dimensional structure and a small ligand molecule, FlexX predicts the geometry of the protein-ligand complex and estimates the binding affinity.
The two main applications of FlexX are complex prediction and virtual screening. Complex prediction is used, when you have a protein and a small molecule binding to it but no structure of the protein-ligand complex. FlexX can be used to create and rank a series of possible protein-ligand complexes. In virtual screening, you have a protein and a set of compounds and you are interested in prioritizing the compounds for experimental testing.
FlexX Features
FlexX is fast. On our protein-ligand benchmark set with about 200 complexes, FlexX takes about 70 seconds per complex prediction on average. The computing time depends on the size of the active site, the size of the ligand, and the degree of ligand symmetry and lies in the range from a few seconds up to twenty minutes.
The conformational flexibility of the ligand is considered. FlexX considers torsion angle flexibility as well as the conformational flexibility of ring systems. In addition, enantiomerism can be handled as a degree of freedom which is important in cases where the set of compounds are automatically created from a 2D database. In the current version of FlexX, the protein is considered rigid.
The placement algorithm in FlexX is based on the interactions occurring between the molecules. This ensures that the search is limited to low-energy structures improving the quality of the results in a given amount of computing time.
FlexX is based on sophisticated physico-chemical models. The MIMUMBA torsion angle database is used for the creation of conformers, an interaction geometry database is used to exactly describe intermolecular interaction patterns. For scoring, the Boehm function (with minor adaptions necessary for docking) is applied.
FlexX Future
FlexX is under ongoing development. We are working on several aspects of protein-ligand docking such as:
Time-efficient docking of combinatorial libraries
Using FlexX in parallel on a heterogeneous workstation cluster
Improving the quality of the described protein-ligand interactions and the scoring
Gramm
Gramm
http://reco3.ams.sunysb.edu/gramm/ GRAMM is a program for protein docking. To predict the structure of a complex, it requires only the atomic coordinates of the two molecules (no information about the binding sites is needed). The program performs an exhaustive 6-dimensional search through the relative translations and rotations of the molecules. The molecular pairs may be: two proteins, a protein and a smaller compound, two transmembrane helices, etc. GRAMM may be used for high-resolution molecules, for inaccurate structures (where only the gross structural features are known), in cases of large conformational changes, etc.
The Global RAnge Molecular Matching (GRAMM) methodology is an empirical approach to smoothing the intermolecular energy function by changing the range of the atom-atom potentials. The technique locates the area of the global minimum of intermolecular energy for structures of different accuracy. The quality of the prediction depends on the accuracy of the structures. Thus, the docking of high-resolution structures with small conformational changes yields an accurate prediction, while the docking of ultralow-resolution structures will give only the gross features of the complex. More information about the GRAMM methodology is on our laboratory research page.
Platforms
GRAMM is compiled on SGI R10000, SGI R4000, SGI R4400, SGI R8000, Sun SPARC, IBM RS6000, DECAlpha, and PC (Windows and Linux). Windows version must work on all 32-bit flavors of the MS Windows operating system. Linux version was compiled on RedHat with glibc2.0.
注册后可免费下载
Hex
http://www.biochem.abdn.ac.uk/hex/ Hex is an interactive protein docking and molecular superposition program. Currently, Hex understands protein and DNA structures in PDB format. Hex was written by Dave Ritchie at the University of Aberdeen.
The main thing which distinguishes Hex from other macromolecular (i.e. protein and DNA) docking programs and molecular graphics packages is its use of spherical polar Fourier correlations to accelerate docking calculations. The graphical nature of Hex came about largely because I wanted to visualise the results of such docking calculations in a natural and seamless way, without having to export unmanageably many (and usually quite big) coordinate files to one of the many existing molecular graphics packages. For this reason, the graphical capabilities in Hex are relatively primitive, although these days one can do quite a lot with a few calls to OpenGL. Nonetheless, if your main interest is in modelling macromolecular docking, Hex may have something new to offer!
Hardware Requirements
Hex will run on most Silicon Graphics and Sun workstations and Linux PC machines. The Linux PC versions are available for RedHat versions 7.0, 7.2, 7.3 and 8.0, but these should run under other Linux distributions.
注册后免费下载
还有许多大型的商业软件包里都有相关的软件，下面的目录比较完整
Protein-protein (peptide) docking
3D-Dock Suite (BioMolecular Modeling, Cancer Research UK)
Bielefeld Protein Docking
BiGGER (BioTecnol, S.A.)
DOT (San Diego Supercomputer Center)
HEX (University of Aberdeen)
GRAMM - Global Range Molecular Matching (SUNY)
Protein-ligand docking
Affinity (Accelrys Inc.)
AutoDock (The Scripps Research Institute)
CombiBUILD (Sandia National Labs)
DockVision (University of Alberta)
FRED - Fast Rigid Exhaustive Docking (OpenEye)
FlexiDock (Tripos)
FlexX (BioSolveIt GmbH)
GLIDE (Schr?dinger GmbH)
GOLD (CDSD)
HINT! - Hydropathic Interactions (Virginia Commonwealth University)
LIGPLOT (University College of London)
SITUS 2.0 (Scripps Research Institute)
VEGA (Milan University)
Protein-protein and protein ligand docking
DOCK (UCSF Molecular Design Institute)
ICM-Dock (MolSoft LLC)
一步一步学计算机辅助药物设计
8. 最后要看一下3D结构，可以用下面这些可视化软件
DS ViewerPro 5.0
最好的结构分子观看软件
有了这个软件，你还用cn3D么？
Accelrys%26#39; Discovery Studio? ViewerPro (DS ViewerPro) combines state of the art molecular graphics with a full range of Windows? desktop integration tools. Using the DS ViewerPro you can visualize and share molecular information in a clear and consistent way, whether it%26#39;s by exchanging chemical files or by including dynamic chemical structures in Word documents, spreadsheets, or presentations
http://www.accelrys.com/dstudio/ds_viewer/ Analyzing Molecular Models
Next: Accessing DataAnalysis and measurement tools help you to evaluate geometry and understand chemistry. Discovery Studio? ViewerPro automatically calculates atomic and molecular properties for molecules sketched or read in. Measurement monitors can be created, all of which are completely dynamic. As your modeling environment changes, your monitors are automatically recalculated. The DS ViewerPro includes additional analysis features. For example, you could investigate potential hydrogen bonds or compute a solvent-accessible surface for a protein structure.
Computational Features:
Calculate:Number of atoms
Molecular formula
Molecular weight
Exact molecular weight
Molecular volume
Partial charge
Measureistances
Angles
Dihedrals Angles
Compute:
3D geometry from 2D
Surfaces
Chirality
Protein secondary structure
Hydrogen bonds
Bumps (contacts between nonbonded atoms)
Rasmol
Rasmol
http://www.umass.edu/microbio/rasmol/ 非常经典的观看生物分子3D结构的软件，免费下载
Chime
MDL Chime
http://www.mdlchime.com/chime/ IE与NetScape浏览器插件,安装后,可以直接用浏览器观看PDB格式的文件,直接在浏览器中观看3D分子。不需RASMOL。
免费下载
9. 再单独介绍几个软件
1. ICM
功能强大的icm
ICM
http://www.molsoft.com/ *Building and validating structural models of protein targets
*Identifying biological ligand binding sites or new sites for allosteric regulation of a protein of interest.
*Evaluating and ranking drug targets, including protein-protein interaction interfaces, designing strategies for rational drug design
*Screening virtual libraries of millions of compounds using the revolutionary Molsoft flexible docking and scoring procedure.
*Identifying interaction hot-spots, i.e. the candidate amino-acid positions involved in protein-protein interactions
*Predicting loop conformations in proteins
*Designing proteins with desired properties
*Docking flexible peptides to proteins
*Designing peptides blocking protein-protein interactions
*2D to 3D conversion, analysis and clustering of large compound libraries,
*Predicting compound properties, building QSAR models, 3D pharmacophore construction and search.
windows下的软件
上官方网站就知道功能有多么强大,不过一般用户没法得到
免费的icm资源
ICM拿不到,但还有些免费的资源可以用一下
Abagyan Lab
http://abagyan.scripps.edu/lab/web/man/frames.htm 据说是ICM的老家,里面有Homology Modeling Server ,可以免费使用,感觉还不错
Molsoft
http://www.molsoft.com/ 官方网站上有两个在线小工具,PDB Viewer 和2D to 3D Molecular Converter 可以使用
ICM Lite
ICM的简化版,免费推出,不过现在官方网站不提供下载了,但可以用google或天网搜一下,说不定还能找到
2.HyperChem 7
软件名称：HyperChem 7
公司主页
http://www.hyper.com/ 平台：Windows
简介：图形界面，有半经验方法（AM1，PM3等），UHF，RHF和CI和7.0版新增加的密度泛函。可进行单点能，几何优化，分子轨道分析，猜测可见-紫外光谱，蒙特卡罗和分子力学计算。主页同时提供试用版下载。
功能：
1. 结构输入和对分子操作。
2. 显示分子。
3. 化学计算。用量子化学或经典势能曲面方法，进行单点、几何优化和过渡态寻找计算。可以进行的计算类型有：单点能，几何优化，计算振动频率得到简正模式，过渡态寻找，分子动力学模拟，Langevin动力学模拟，Metropolis Monte Carlo模拟。支持的计算方法有：从头计算，半经验方法，分子力学，混合计算。
4. 可以用来研究的分子特性有：同位素的相对稳定性；生成热；活化能；原子电荷；HOMO-LUMO能量间隔；电离势；电子亲和力；偶极矩；电子能级；MP2电子相关能；CI激发态能量；过渡态结构和能量；非键相互作用能；UV-VIS吸收谱；IR吸收谱；同位素对振动的影响；对结构特性的碰撞影响；团簇的稳定性。
5. 支持用户定制的外部程序。
6. 其它模块：RAYTRACE模块，RMS Fit，SEQUENCE编辑器，晶体构造器；糖类构造器，构像搜寻，QSAR特性，脚本编辑器。
7. 新的力场方法：Amber 2，Amber 3，用于糖类的Amber，Amber 94，Amber 96。
8. ESR谱。
9. 电极化率。
10. 二维和三维势能图。
11. 蛋白质设计。
12. 电场。
13. 梯度的图形显示。
14. 新增功能：密度泛函理论(DFT)计算；NMR模拟；数据库；Charmm蛋白质模拟；半经验方法TNDO；磁场中分子计算；激发态几何优化；MP2相关结构优化；新的芳香环图；交互式参数控制；增强的聚合物构造功能；新增基组。
3.Triton
我的理解它可以做酶分子的进化,不只到说的对不对
TRITON
http://ncbr.chemi.muni.cz/triton/ The program TRITON is graphical tool for modelling protein mutants and assessment of their activities. Protein mutants are modelled based on the wild type structure by homology modelling using the external program MODELLER. Chemical reactions taking place in the mutants active site are modelled using the semi-empirical quantum mechanic program MOPAC. Semi-quantitative predictions of mutants activities can be achieved by evaluating the changes in energies of the system and partial atomic charges of the active site residues during the reaction. The program TRITON offers graphical tools for the preparation of the input data files, for calculation and for the analysis of the generated output data. Implementation ensures the overall integrity of consecutive steps of the modelling of mutants and calculation of reaction coordinates, but the program can also be used simply for combinatorial generation of multiple mutants by homology modelling.
------------------------------------------------
以下转自biolover
biohity: 我鼓励作者Martin Prokop在新版中支持Mopac2002(原来他只想支持mopac2000)，他做到了。但因为是alpha版，有很多bugs。正一个个向他指出呢。
alchemy: 应该是好东西，遗憾的是好东西都要在irix/linux上跑
Bac: 我的熟悉是，MOPAC是用半经验的量子化学方法计算突变部位的变化的。输入是氨基酸残基的改变（结构的改变）。运行后得到应该是突变部位原子能量和电荷的变化。进而算出活化能的变化。不知道理解得对不对，我想最好还是请Alchemy再给我们说说。
qianfeng:这个软件是否是这样运行的,先要输入酶的晶体结构，再输入你要突变的位点，它用modeller做homology modelling，得到突变后的酶分子结构，再用MOPAC计算突变部位原子能量和电荷的变化。进而算出活化能的变化。
还有几点没搞清楚
1 酶催化的活性部位以及催化过程好象是要自己输入的，不是软件分析的？这样的话必须对这个酶的性质非常的清楚
2 最后得到的是活化能的变化，并不是表观的酶活？
3 它应该可以用于酶分子的rational design，但好象只能猜测酶活，能否猜测其它性质，如酶的稳定性？
4.CAChe Group 软件介绍
有CAChe 5.0 和 BioMedCAChe
CAChe Group 软件介绍
http://www.cachesoftware.com/ CAChe 5.0 for Windows is a leading computer-aided chemistry modeling package for experimental chemists conducting research in life sciences, materials and chemicals, as well as for undergraduate and graduate educators. The new Version 5.0 includes a new semiempirical method with 4x greater accuracy than current methods, challenging even experimental accuracy; modeling of molecules with up to 20,000 atoms; the inclusion of all main group elements in one semiempirical method; and more.
BioMedCAChe is the new computer-aided chemistry software package designed specifically for bio- and medicinal chemists. The package aids researchers in discovering structure-activity relationships, optimizing leads by maximizing activity, and improving the prediction of bioavailability. The power of the package enables researchers to predict properties of compounds that have never been made or properties that have never been measured. This prediction enables researchers to select those novel compounds for testing or synthesis that are most likely to be successful, saving valuable lab time and resources. BioMedCAChe also offers users the ability to devise ways to calculate molecular properties and calibrate them to experimental results.
均可下载免费试用
5.ChemOffice
ChemOffice Ultra 2002
http://chemstore.cambridgesoft.com/ ChemOffice, the chemistry software suite that redefined the chemist%26#39;s desktop, transforms your PC into a chemical publishing, modeling, and database workstation.
This ultimate suite includes ChemDraw Ultra 7.0, Chem3D Ultra 7.0 and ChemFinder Ultra 7.0. It adds E-Notebook Ultra 7.0, BioAssay Pro 7.0, MOPAC, Gaussian %26 GAMESS interfaces, ChemSAR Server Excel, CLogP, Purchasing for Excel, CombiChem/Excel, and even more, as well as the full set of ChemInfo databases, including ChemACX %26 ChemACX-SC, The Merck Index and ChemMSDX, to ChemOffice Pro.
Top Ten New %26 Popular Features
E-Notebook Ultra 7.0 - (W) Makes electronic laboratory journals a reality. Stores collections of pages created with ChemDraw, Microsoft Excel and Word.
BioAssay Pro 7.0 - (W) Integrate chemical and biological data. Query by structure or text with ChemFinder and set up Excel templates for reporting and graphing.
The Merck Index 13th Electronic Edition - (W) An encyclopedia of chemicals, drugs and biologicals with over 10,000 monographs on single substances or groups of related compounds.
ChemACX %26 ChemACX-SC 7.0 - (W) 300 catalogs from leading chemical suppliers, including Sigma-Aldrich, Fisher, Acros, Alfa Aesar, Lancaster and TCI America, providing rapid ordering information for over 450,000 products. ChemACX-SC is a collection of fully searchable catalogs from leading screening compound suppliers.
Polymer Draw - (W, M) Represent and manipulate polymers in ChemDraw.
BioArt - (W, M) A palette of customizable common biochemistry symbols including membranes, cellular structures and more.
ChemDraw/Excel 7.0 - (W) Display and perform calculations on up to 1,400 chemical structures at a time in Excel.
Name=Struct - (W, M) Generate a ChemDraw structure by typing in systematic chemical names for most substances.
Purchasing for Excel - (W) Create shopping lists of compounds in Excel for automated chemical purchasing.
ChemFinder/Word - (W) Use ChemFinder as an extension of MS Excel and Word for Windows to create structure searchable spreadsheets and documents with an embedded ChemDraw application.
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