Contents 1 Open-Source Tools, Techniques, and Data in Chemoinformatics

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Transcription:

Contents 1 Open-Source Tools, Techniques, and Data in Chemoinformatics... 1 1.1 Chemoinformatics... 2 1.1.1 Open-Source Tools... 2 1.1.2 Introduction to Programming Languages... 3 1.2 Chemical Structure Representation... 8 1.3 Code for Including the Editor Applet in JChemPaint... 9 1.4 Definition of Templates (Polygons, Benzene, Bond, Atom, etc.)... 9 1.5 Free Tools... 10 1.6 Academic Programs... 11 1.6.1 Marvin Sketch... 11 1.6.2 ACD Labs... 12 1.7 Commercial Tools... 12 1.7.1 ChemDraw... 12 1.7.2 Schrodinger... 14 1.7.3 MOE (CCG)... 14 1.7.4 Accelrys... 14 1.8 A Practice Tutorial... 15 1.8.1 Interconversion of Name/SMILES to Structure and Vice Versa... 15 1.9 Introduction to Chemical Structure Formats... 20 1.9.1 Linear Format... 20 1.9.2 Graph-based Representation (2D and 3D formats)... 21 1.9.3 Connection Tables... 22 1.9.4 FILE FORMATS... 22 1.10 2D and 3D Representation... 30 1.10.1 Code for 3D Structure Generation in ChemAxon... 31 1.10.2 A Practice Tutorial... 31 1.11 Abstract Representation of Molecules... 32 1.12 File Format Exchange... 35 1.12.1 A Practice Tutorial... 36 1.12.2 Code for Reading a Molecule, checking the Number of Atoms, and Writing a SMILES String... 38 xiii

xiv Contents 1.12.3 Code for Reading a SMILES String in Python... 39 1.13 Similarity and Fingerprint Analysis... 39 1.13.1 Simple Fingerprints (Structural Keys)... 41 1.13.2 Hashed Fingerprints... 42 1.13.3 A Practice Tutorial... 44 1.14 Molecular Similarity... 45 1.14.1 Exact Structure Search... 46 1.14.2 Substructure Search... 47 1.14.3 Similarity Search... 48 1.14.4 Subsimilarity Search... 50 1.15 Search for Relationship... 51 1.16 Similarity Measures... 52 1.17 Molecular Diversity... 55 1.18 Advanced Structure-handling Tools... 56 1.18.1 CCML... 56 1.19 ChemXtreme... 56 1.19.1 Barcoding SMILES... 57 1.19.2 Chem Robot... 57 1.19.3 Image to Structure Tools... 58 1.19.4 CLide... 59 1.19.5 Advanced Structure Computation Platforms... 59 1.20 Virtual Library Enumeration... 59 1.21 Clustering... 60 1.22 Databases... 60 1.22.1 Database Server My SQL... 62 1.22.2 Code for Connecting to a MySQL Database... 63 1.22.3 A Practice Tutorial... 64 1.22.4 Creating and Hosting Database... 67 1.22.5 A Practice Tutorial... 67 1.22.6 Hosting the Database... 71 1.22.7 Chemical Databases... 74 1.22.8 Do It Yourself (DIY)... 85 1.22.9 Questions... 89 References... 89 2 Chemoinformatics Approach for the Design and Screening of Focused Virtual Libraries... 93 2.1 Introduction to Structure Property Correlations... 93 2.1.1 Descriptors... 94 2.1.2 Online Property Prediction Tools... 108 2.1.3 Virtual Library Generation (Enumeration)... 111 2.1.4 Virtual Screening... 121 2.1.5 Thumb Rules for Computing Molecular Properties... 128 2.1.6 Do it Yourself... 128 2.1.7 Questions... 129 References... 129

Contents xv 3 Machine Learning Methods in Chemoinformatics for Drug Discovery... 133 3.1 Introduction... 133 3.2 Machine Learning Models for Predictive Studies... 134 3.3 Machine Learning Methods... 136 3.4 Open-Source Tools for Building Models for Drug Design... 139 3.4.1 Library for Support Vector Machines (LibSVM)... 139 3.4.2 Waikato Environment for Knowledge Analysis (WeKa)... 141 3.4.3 R Program... 151 3.5 Free Tools for Machine Learning... 152 3.5.1 An Example of SVR-based Machine Learning... 152 3.5.2 Rapid Miner... 160 3.6 Commercial Tools for Building ML Models... 164 3.6.1 Molecular Operating Environment (MOE)... 164 3.6.2 IBM SPSS... 176 3.6.3 Matrix Laboratory (MATLAB)... 178 3.7 Genetic Programming-Based ML Models... 179 3.7.1 A Practical Demonstration of GP-Based Software... 185 3.8 Thumb Rules for Machine Learning-Based Modelling... 189 3.9 Do it Yourself (DIY)... 191 3.10 Questions... 191 References... 192 4 Docking and Pharmacophore Modelling for Virtual Screening... 195 4.1 Introduction... 195 4.2 A Practice Tutorial: Docking Using a Commercial Tool... 196 4.3 Docking Using Open Source Software... 211 4.3.1 Autodock Steps... 212 4.3.2 Docking Using AutoDock Vina... 220 4.4 Other Docking Algorithms... 223 4.4.1 Induced Fit Docking... 224 4.4.2 Flexible Protein Docking... 225 4.4.3 Blind Docking... 226 4.4.4 Cross Docking... 226 4.4.5 Docking and Site-Directed Mutagenesis... 229 4.5 Protein Protein Docking... 231 4.6 Pharmacophore... 234 4.6.1 Pharmacophore Modelling in SCHRÖDINGER... 235 4.6.2 Finding Pharmacophore Features Using MOE... 248 4.7 Open Source Tools for Pharmacophore Generation... 253 4.8 Rules of Thumb for Structure-Based Drug Design... 254 4.9 Do it Yourself Exercises... 260 4.10 Questions... 261 References... 267

xvi Contents 5 Active Site-Directed Pose Prediction Programs for Efficient Filtering of Molecules... 271 5.1 Introduction... 271 5.2 A Practice Tutorial for Predicting Active Site Using SiteMap... 272 5.3 A Practice Tutorial for Active Site Prediction Using MOE... 276 5.4 Free Online Tools for Active Site Prediction... 279 5.5 Homology Modelling... 282 5.6 A Practice Tutorial for Homology Modelling... 285 5.7 Model Validation Using Online Servers... 295 5.8 Receptor-Based Pharmacophore... 296 5.9 Studies on Active Site Structural Features... 298 5.9.1 Application of Active Site Features in Chemoinformatics... 300 5.10 Thumb Rules for Active Site Identification and Homology Modelling... 312 5.11 Do it Yourself Exercises... 313 5.12 Questions... 313 References... 313 6 Representation, Fingerprinting, and Modelling of Chemical Reactions... 317 6.1 Introduction... 318 6.2 Reaction Representation in Computers... 318 6.3 Computational Methods in Reaction Modelling... 318 6.3.1 Empirical and Semiempirical Methods... 319 6.3.2 Molecular Mechanics Methods... 320 6.3.3 Molecular Dynamics Methods... 321 6.3.4 Statistical Mechanics and Thermodynamics... 321 6.3.5 The Quantum Mechanical/molecular Mechanical Approach... 322 6.3.6 Modelling the Transition State of Reactions... 322 6.4 TS Modelling of Organic Transformations... 324 6.4.1 Name Reactions... 324 6.4.2 A Practice Tutorial for Transition State and Intrinsic Reaction Coordinate Modelling... 326 6.4.3 A Practice Tutorial Using Maestro Jaguar... 338 6.4.4 A Practice Tutorial Using Spartan... 344 6.5 Reaction-Searching Approaches and Tools... 347 6.5.1 Chemical Ontologies Approach for Reaction Searching... 351 6.5.2 Reaction Searching Using Fingerprints-Based Approach... 354 6.5.3 Tools for Reaction Searching... 359 6.6 Reaction Databases... 363 6.6.1 Tools for Reaction Library Enumeration... 364 6.6.2 A Practice Tutorial... 365 6.7 Artificial Intelligence in Chemical Synthesis... 366 6.8 Modelling Enzymatic Reactions... 369

Contents xvii 6.9 Thumb Rules for Performing Reaction Representation, Fingerprints, and Modelling... 369 6.10 Do it Yourself... 371 6.11 Questions... 371 References... 371 7 Predictive Methods for Organic Spectral Data Simulation... 375 7.1 Introduction... 376 7.2 Fragment-Based Drug Discovery... 378 7.3 Spectra Prediction Methods... 384 7.4 Spectra Prediction Tools... 384 7.5 Open-Source Tools... 385 7.5.1 GAMESS... 385 7.6 Proprietary Tools... 385 7.6.1 ACD/NMR Predictors... 385 7.6.2 Cambridgesoft Chem3D... 385 7.6.3 Jaguar... 385 7.6.4 Gaussian... 390 7.6.5 ADF... 391 7.6.6 MestreNova... 392 7.6.7 Spartan... 396 7.6.8 Spectral Databases... 399 7.7 Spectra Viewer Programs... 404 7.8 In-House Tools for Spectra Prediction... 404 7.9 Code to Generate Proton and Carbon NMR Spectrum... 406 7.10 Thumb Rules for Spectral Data Handling and Prediction... 409 7.11 Do it Yourself... 410 7.12 Questions... 411 References... 412 8 Chemical Text Mining for Lead Discovery... 415 8.1 What is Text Mining?... 416 8.1.1 Text Mining vis-a-vis Data Mining... 416 8.1.2 A Snippet of Java Code Using the Above URL... 418 8.2 What are the Components of Text Mining?... 419 8.3 Text-mining Methods... 421 8.3.1 Statistics/ML-based Approach... 422 8.3.2 Rule-based Approach... 423 8.4 Why Text Mining... 424 8.5 General Text-mining Tools... 424 8.5.1 A Practice Tutorial with an Open-source Tool... 425 8.5.2 R Program for Text Mining... 430 8.6 Free Tools for Text Mining... 434 8.7 Biomedical Text Mining... 434 8.8 Chemically Intelligent Text-mining Tools... 435

xviii Contents 8.9 In-house Tools for Text-mining Applications for Chemoinformatics... 437 8.9.1 Java Code Snippet for Data Distribution... 441 8.10 Thumb Rules While Performing and Using Text-mining Results... 445 8.11 Do it Yourself... 445 8.12 Questions... 445 References... 445 9 Integration of Automated Workflow in Chemoinformatics for Drug Discovery... 451 9.1 What is a Workflow?... 451 9.2 Need for Workflows... 452 9.3 General Workflows in Bioinformatics... 453 9.4 General Workflows in Chemistry Domain... 453 9.4.1 Accelrys Pipeline Pilot... 453 9.4.2 IDBS Chemsense (Inforsense Suite)... 454 9.4.3 CDK Taverna... 455 9.4.4 KNIME... 455 9.4.5 Workflow Examples... 467 9.4.6 Workflow for QSAR (Anti-cancer)... 469 9.5 Schrodinger KNIME Extensions... 470 9.5.1 A Practice Tutorial... 473 9.6 Other KNIME Extensions... 481 9.6.1 MOE(CCG)... 481 9.6.2 ChemAxon... 483 9.7 Protein Ligand Analysis-Based Workflows for Drug Discovery... 483 9.7.1 A Practice Tutorial for Protein Ligand Fingerprint Generation... 486 9.8 Prolix... 489 9.9 J-ProLINE: An In-house-developed Chem-Bioinformatics Workflow Application... 489 9.10 Targetlikeness Score... 496 9.11 Databases and Tools... 496 9.12 Thumb Rules for Generating and Applying Workflows... 496 9.13 Do it Yourself... 497 9.14 Questions... 497 References... 497 10 Cloud Computing Infrastructure Development for Chemoinformatics... 501 10.1 What is a Portal?... 501 10.2 Need for Development of Scientific Portals... 502 10.3 Components of a Portal... 502 10.4 Examples of Portal Systems... 503

Contents xix 10.5 A Practice Tutorial for Portal Creation... 504 10.5.1 Custom Database connection and Display Table with Paginator via portlet in Liferay Portal... 509 10.6 A Practice Tutorial for Development of Portlets for Chemoinformatics... 512 10.6.1 Marvin Sketch Portlet... 512 10.6.2 JME Portlet... 515 10.6.3 Jchempaint Portlet... 515 10.7 Mobile Computing... 516 10.7.1 Android Applications for Chemoinformatics... 517 10.8 Need of High-Performance Computing in Chemoinformatics... 526 10.9 Thumb Rules for Developing and Using Scientific Portals and Mobile Devices for Computing... 526 10.10 Do it Yourself Exercises... 526 10.11 Questions... 527 References... 527 Index... 529

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