The SGI computers that you are sitting at are fairly old and not too good at running calculations. However, they serve well as graphical terminals that allow connection to remote workstations that handle the modeling tasks. We have three workstations available, each with own set of software tools. The workstations are called drug1, drug2, and drug3 and are based on a popular Linux operating system. You will be using mainly the workstation called "drug1" today. To connect to this workstation, simply type drug1 on the Unix shell. This opens a Secure Shell connection to the workstation and allows graphical display of remote programs on your screen. Some programs that you will be using remotely in this course are the web browser Firefox, text editor nedit, scientific data analysis program Xmgrace and molecular structure editor MOLDEN. Some molecular visualization programs, such as PyMOL rely heavily on the graphics card associated with the display device and will be too slow for remote use. For now, start Firefox browser by typing firefox on the remote shell. Remember that most Unix commands are lowercase.
Structures of molecules can be determined experimentally or predicted computationally. For small molecules, such as ethanol and cyclohexane, both spectroscopic methods and rigorous quantum chemical computations can provide highly accurate molecular geometries in the vapor phase. Such highly accurate methods are not readily applicable for most drug molecules due to their larger size. However, experiments can give quite accurate structures of drugs in the crystalline state or while bound to target macromolecules. Approximate computations can give sufficiently accurate structures for drugs in the gas or liquid phase. Often, the effects of the medium on the structure are not too significant; in this case use of experimental crystal structures or computationally predicted gas phase structures is permissible for description of molecules in solution. In other cases, care must be taken to use advanced computational methods that account for effects of the environment.
Databases such as Klotho provide model structures for many common small molecules. Chemicals with Pharmaceutical Activity from University of Oxford offers access to many drug models and the Protein Data Bank offers access to experimentally determined structures of macromolecules and macromolecular complexes. The PDB provides powerful search and browse functions based on a variety of criteria. For example, one can browse for macromolecular structures that are associated with a particular disease. To download a structure file from the PDB, first click on the title line to get to the summary page about this macromolecule, then click on the download icon next to the PDB code to download the uncompressed file. Alternatively, you can download the compressed file in the gzip format, which can be uncompressed by using the Unix command gunzip. Some molecular visualization and modeling programs allow to fetch PDB files directly from within the program.
Several web sites generate 3D molecular structures from the SMILES string using the program CORINA. CORINA uses built-in tables of standard bond lengths and angles to create a reasonable model for small or rigid molecules. However, the model geometry for larger and flexible molecules is likely to be quite different than the most prevalent geometry in aqueous solution. Use the Online SMILES Translator by National Institutes of Health. At the website, enter the SMILES string for ethanol in the Input Format field, select PDB and 3D for output formats, and hit Translate. Save the file as ethanol.pdb in your directory. Close Firefox browser and verify that the file ethanol.pdb is in your directory by examining the output of the Unix command ls -l.
Most chemists are well familiar with drawing 2D molecular structures and several programs allow effortlessly draw 2D representations of three-dimensional molecules. Two of the most popular 2D chemical diagram editors for Windows and MacOS systems are ChemDraw from CambridgeSoft and MDL Draw from Elsevier MDL. Students can download a fully functional free chemical drawing program MDL Isis/Draw from Elsevier MDL website after registration. An Open Source program JChemPaint is installed on the workstations. Some chemical drawing tools allow generation and export of 3D coordinates of the drawn molecule. The JME Molecular Editor allows to sketch simple molecules on-line and export these structures into the SMILES string.