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Graphical-Automatic Drug Design System for Docking, Screening and Post-Analysis

Graphical-Automatic Drug Design System for Docking, Screening and Post-Analysis Windows‧Linux iGEMDOCK Documentation iGEMDOCK 2 Copyright © 2008 Drug Design and Systems Biology Laboratory of National Chiao Tung University, Taiwan 3 Contacting User Support If you have a technical problem with our iGEMDOCK you can contact our research group in Taiwan. Department of Biological Science and Technology & Institute of Bioinformatics National Chiao Tung University Name: Dr. Jinn-Moon Yang Address: 75 PO-Ai Street, Hsinchu, Taiwan, 30050, ROC Office & Lab : 308 and 304 (Lab) in Experiment Building Tel: 886- 3-5712121 ext.56946 Fax: 886-3-5729288 E-mail: moon@faculty.nctu.edu.tw Or Come to our web site: http://gemdock.life.nctu.edu.tw/dock/ 4 CONTENTS I INTRODUCTION............................................................................................................6 II INSTALLATION..............................................................................................................8 1 SYSTEM REQUIREMENTS...................................................................................................8 2 IN WINDOWS XP/VISTA ....................................................................................................8 3 IN LINUX........................................................................................................................ 11 III GETTING START..........................................................................................................13 1 OVERVIEW......................................................................................................................13 2 BINDING SITE PREPARATION............................................................................................15 3 LIGAND PREPARATION....................................................................................................18 4 RUNNING IGEMDOCK .................................................................................................19 Setup output path..............................................................................................................19 Setup the GA Parameters .................................................................................................19 Advance Options...............................................................................................................20 Start Docking....................................................................................................................21 5 POST-ANALYSIS IN IGEMDOCK....................................................................................23 Loading binding site.........................................................................................................23 Loading docked poses.......................................................................................................24 Generating interaction profile..........................................................................................24 Cluster based analysis......................................................................................................26 Save post-analysis data ....................................................................................................27 The output data of iGEMDOCK.......................................................................................28 Importing your data to excel for advanced study.............................................................28 IV ADVANCED FEATURES..............................................................................................30 BINDING SITE PREPARATION ..................................................................................................30 1. iGEMDOCK can not help me to prepare my binding site when my protein file is not original PDB file or has no ligand. How can I prepare my binding site under these 5 situations?.........................................................................................................................30 2. My protein target needs to consider the cofactor or metal ion in docking calculation. Can iGEMDOCK recognize these non-amino acid molecules in the docking calculation? ...................................................................................................................................34 LIGAND LIBRARY PREPARATION.............................................................................................35 3. I want to prepare the bounded ligand from PDB. How can I make it?.....................35 4. I want to construct ligands/ligand library for screening. Is there any example? .....43 SCORING FUNCTION OF IGEMDOCK....................................................................................54 5. I want to re-score my ever predicted poses against a protein target. How to do it?.54 6. What is the meaning of each term in GEMDOCK interaction profile?....................57 7. What is the pharmacological consensus method mentioned in Proteins: Structure, Function, and Bioinformatics, vol. 59, pp. 205-220, 2005 ? How to use these terms in my screening?.........................................................................................................................59 COMMAND MODE OF IGEMDOCK .......................................................................................63 8. Using the command mode in iGEMDOCK ...............................................................63 V FAQ..................................................................................................................................66 1 INSTALLATION ................................................................................................................66 2 RUN DOCKING ................................................................................................................66 6 I Introduction Structure-based virtual screening and post-screening analysis are emergent tasks in computer-based drug discovery. Combining these two methods to effectively reduce the false positives from a large compound database is considered as a key step to finding the lead compounds. In this study, we have developed a graphical-automatic drug discovery system, called iGEMDOCK, for integrating docking, screening, post-analysis, and visualization. To our best knowledge, iGEMDOCK is the first system for this requirement. The core of iGEMDOCK is the GEMDOCK, which is a robust and well-developed tool. Using iGEMDOCK, the predicted poses generated from the GEMDOCK are able to be directly visualized by a molecular visualization tool and analyzed by post-analysis tools. iGEMDOCK provides the post-analysis tools by using k-means and hierarchical clustering methods based on the docked poses (i.e. protein-ligand interactions) and compound properties (i.e. atomic compositions). Atomic composition (AC), which is similar to the amino acid composition of a protein sequence, is a new concept for measuring compound similarity. We validated the protein-ligand docking accuracy and screening accuracies of iGEMDOCK by using a test set with 100 protein-ligand complexes and four targets, respectively, which are thymindine kinase, estrogen receptor for antagonists and agonists, and human DHFR. Experimental results show that iGEMDOCK keeps the advantages of GEMDOCK and provided graphical-integrated environment for virtual screening and docking. We also evaluated the AC method on a test set with 76 compounds. The results indicate that the AC method performs better than the comparative methods in this set. We believe that iGEMDOCK, which integrates the structure-based virtual screening and post-screening analysis, is a useful system for drug discovery. The core of iGEMDOCK is the GEMDOCK. Based on GEMDOCK, we have been published primary references and some applications. These articles would be helpful for using iGEMDOCK. Primary references 1. J.-M. Yang* and C.-C. Chen, "GEMDOCK: A generic evolutionary method for molecular docking," Proteins: Structure, Function, and Bioinformatics, vol. 55, pp. 288-304, 2004. 2. J.-M. Yang* "Development and evaluation of a generic evolutionary method for protein-ligand docking," Journal of Computational Chemistry, vol. 25, pp. 843-857, 2004. 3. J.-M. Yang* and T.-W. Shen, "A pharmacophore-based evolutionary approach for screening selective estrogen receptor modulators," Proteins: Structure, Function, and Bioinformatics, vol. 59, pp. 205-220, 2005. 4. J.-M. Yang* Y.-F. Chen, T.-W. Shen, B. S. Kristal, and D. F. Hsu, "Consensus Scoring Criteria for Improving Enrichment in Virtual Screening," Journal of Chemical Information and Modeling, vol. 45, pp. 1134-1146, 2005. 7 Selected applications Virtual screening 1. J.-M. Yang, Y.-F. Chen, Y.-Y. Tu, K.-R. Yen, and Y.-L. Yang*, “Combinatorial computation approaches identifying tetracycline derivates as flaviviruses inhibitors,” PLoS ONE, pp. e428.1- e428.12, 2007. 2. H.-C. Hung, C.-P. Tseng, J.-M. Yang, Y.-W Ju, S.-N. Tseng, Y.-F. Chen, Y.-S. Chao, H.-P. Hsieh, S.-R. Shih, John T.-A. Hsu, "Aurintricarboxylic acid inhibits influenza virus neuraminidase," Antiviral Research, vol.81, pp. 123-131, 2009 Binding site prediction 1. M.-C. Yang, H.-H. Guan, M.-Y. Liu, Y.-H. Lin, J.-M. Yang, W.-L. Chen, C.-J. Chen, and Simon J. T. Mao*, "Crystal structure of a secondary vitamin D3 binding site of milk ß-lactoglobulin," Proteins: Structure, Function, and Bioinformatics, vol. 71, pp. 1197-1210, 2008. 2. M.-C. Yang, H.-H. Guan, J.-M. Yang, C.-N. Ko, M.-Y. Liu, Y.-H. Lin, C.-J. Chen, and Simon JT Mao*, "Rational Design for crystallization of b-Lactoglobulin and vitamin D3 complex: reveal of a secondary binding site," Crystal Growth & Design, vol. 8, pp. 4268-4276, 2008. This user guide includes basic operation and advanced features for iGEMDOCK users. We help our user guide can provide a fast and low-learning curve experience for starting iGEMDOCK. If you are familiar with iGEMDOCK, we suggest that you can start from section IV: advance features. This part describes how to do something which is important for virtual screening. If you have some troubles at using iGEMDOCK, you can try to look for the solutions in our FAQ (section V). We collect some frequently asked questions and solutions here for our users. 8 II Installation iGEMDOCK is currently distributed via email or website download. Currently, it is available for free and non-commercial researches. You can visit our web site (http://gemdock.life.nctu.edu.tw) to download the iGEMDOCK archives depending on your machine. We illustrate the installation steps on Microsoft windows XP/Vista and Linux. It is easy to install iGEMDOCK on your system. Create a directory for the iGEMDOCK and extract compressed files into this directory. Then, you can start to use iGEMDOCK. 1 System requirements Windows® Linux Operation system Windows® XP/Vista Suse 9 (64bit) / CentOS 5 (32bit) / Ubuntu 8 (32bit) CPU Pentium 1 GHz or higher processor Pentium 1 GHz or higher processor Disk space 40 MB or higher 40 MB or higher Monitor resolution 1024x768 or higher resolution 1024x768 or higher resolution Download iGEMDOCK: http://gemdock.life.nctu.edu.tw/dock/download.php 2 In windows XP/Vista 1. Downloading the iGEMDOCK from http://gemdock.life.nctu.edu.tw/dock/download/iGemdock.zip and extracting the iGEMDOCK.zip 2. Selecting a folder to extract files 9 3. Finding the folder “\bin” in decompressed folder (e.g. C:\iGemdock\bin) 4. Executing the executable file with gem icon (iGemdock.exe) to start your docking/screening task. 10 11 3 In Linux 1. Downloading the iGEMDOCK from http://gemdock.life.nctu.edu.tw/dock/igemdock.php and extracting the downloaded file. Select the iGEMDOCK according to your Linux distribution. We currently release the binary files for 32 bit and 64 bit Linux system. You can download the iGEMDOCK distribution depending on your system. If there is no released version for your Linux distribution, you can contact us for help. 64 bit Linux system iGEMDOCK binary file Suse Linux 9 iGemdock—Suse9-Linux-x_64.tar 32 bit Linux system iGEMDOCK binary file CentOS 5 iGemdock—CentOS5-Linux.tar Ubuntu 8 iGemdock—Ubuntu8-Linux.tar 2. Typing “tar -xf iGemdock-*-Linux.tar” in terminal or double click the compressed file to extract it. For example: the command on Ubuntu 8 >tar –xf iGemdock--Ubuntu8-Linux.tar Or 3. Changing the mode of the files in “/bin”. >chmod 755 iGemdock/bin/* 4. Executing the script, iGemdock.sh in “/bin” to start 12 iGEMDOCK. >cd iGemdock/bin/ >./iGemdock.sh 13 III Getting start 1 Overview iGEMDCOK is a suite of automated docking/screening tools. The interface of iGEMDOCK has two main tags, docking/screening tag and post-analyzing tag (shown as Figure A and C, respectively). The docking/screening tag (Figure A) is designed to predict how chemical molecules bind to a receptor of known 3D structure. The predicted protein-ligand poses can be further performed post-analysis in the post-analyzing tag (Figure C). This can help, for example, to guide biological researchers explore better binders. The architecture of iGEMDOCK consists of four major modules. The docking/screening and post-analyzing modules contain several components to make the screening/analyzing procedure smoothly. The predicted or clustered protein-ligand complexes can be visualized in the visualization module. The parallel processing module provides the parallel computation of screening jobs. The tools in the docking/screening and post-analyzing modules are further introduced as followed. 14 Components of docking/screening module • mod_cav : this program generates the binding site from the ligand bounded PDB file. • mod_lig : this program uploads/Finance/ igemdock-guide.pdf