1. www.consorzio-cometa.it FESR Consorzio COMETA - Progetto PI2S2 Molecular Modelling Applications Laura Giurato Gruppo di Modellistica Molecolare (Prof. S.Guccione), Dip.Scienze Farm.,Catania Consorzio COMETA Grid Tutorial per l’Università di Palermo Palermo, 12 Dicembre 2007

2. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 2 Basics Docking is most commonly used in the field of drug design (most drugs are small organic molecules): it’s a computational method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex.

3. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 3 Basics Docking may be applied to: Hit identification - docking combined with a scoring function can be used to quickly screen large databases of potential drugs in silico to identify molecules that are likely to bind to protein target of interest. Lead optimization - docking can be used to predict in where and in which relative orientation a ligand binds to a protein (also referred to as the binding mode or pose). This information may in turn be used to design more potent and selective analogues.

4. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 4 Basics How can we filter down the enormous chemical space (~10 60 compounds) to a manageable number of potential drugs that can be tested? Virtual screening involves the rapid assessment of large libraries of chemical structures in order to guide the selection of likely drug candidates. The main goal of a virtual screen is to come up with hits of novel chemical structure that yield a unique pharmacological profile.

5. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 5 Molegro Virtual Docker http://www.molegro.com/ Molegro Virtual Docker (MVD) is an integrated platform for predicting protein-ligand interactions. Basic Features Docking search algorithm based on state-of-the-art genetic algorithms Console command interface to allow for advanced user interaction Support for batch jobs – distribute the docking simulations on multiple computers Support for scripting of the docking engine (Python wrapper included) Supported Platforms Windows Vista, XP, 2003, and 2000 Mac OS X 10.3.9 or later (Intel and PPC) Linux 32 & 64 bit: Most standard distributions (including Fedora Core 3,4 and 5, Gentoo 2005.1, Red Hat Enterprise Linux AS 3 and AS 4, SUSE Linux 10, Ubuntu Linux 5.10, 6.10)

6. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 6 Molegro Virtual Docker http://www.molegro.com/ The Docking Wizard in the MVD graphical user interface was designed to handle a limited number of ligands (less than a thousand). For larger docking runs, it is possible to script the docking engine using the built-in scripting language or external scripting languages (such as Python). This also allows to distribute larger docking runs across several machines. The MVD graphical user interface is capable of importing and analysing very large numbers of docked poses. The MVD license permits the user to install and run MVD on an unlimited number of machines or CPU's. There is no additional 'per-cpu' cost involved.

7. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 7 Molegro Virtual Docker http://www.molegro.com/ Splitting Docking Runs Into Multiple Runs. This script can be used to divide the workload between different machines: // Init with appropriate settings first... DOCKSETTINGS maxIterations=1000;runs=10;MaxPoses=5 EVALUATOR cropdistance=0;hbond90=true;water=true OPTIMIZER cavity=true;popsize=50;crossoverrate=0.9;keepmaxposes=5 // For machine 1: LOAD C:\BENCHMARK\1HVR.mvdml IMPORT LIGAND[0-99] FROM DB.sdf DOCK // For machine 2: LOAD C:\BENCHMARK\1HVR.mvdml IMPORT LIGAND[100-199] FROM DB.sdf DOCK

8. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 8 Molegro Virtual Docker http://www.molegro.com/ Running the Script Interface Interactively: MVD can also run in interactive mode. To start MVD in interactive mode, use the following syntax: Example: mvd -interactive The purpose of the interactive mode is to allow scripting languages capable of writing to and from the standard input and output of a program to control the docking process. This can be useful for automating larger docking runs. When in interactive mode, MVD will send an '[DONE]: ' after each command has been interpreted.

9. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 9 Cresset technology http://www.cresset-bmd.com/ An alternative approach to docking for virtual screening is based on molecular fields: Compounds showing a similar molecular field pattern are likely to bind at the same target site regardless of their underlying structure possibility to find novel chemotypes

10. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 10 FieldAlign http://www.cresset-bmd.com/fieldalign.shtml Given a 3D template molecule, FieldAlign can align other molecules entered in 2D to that template rapidly and in a biologically-relevant manner. FieldAlign is available as a Linux or Windows GUI program. A Linux command line version is also available which can be readily customized by expert users. The molecules that have to be aligned to the reference should be present in 2D in an sdf, mol2 or xed file. The total number of molecules is limited to 200. To align many more molecules than this then a command line version of FieldAlign is available.

11. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 11 Basics Conformational energy searching is used to find all of the energetically preferred conformations of a molecule (especially rotamers), which is mathematically equivalent to locating all of the minima of its energy function. Molecular dynamics (MD) is a form of computer simulation wherein atoms and molecules are allowed to interact for a period of time under known laws of physics, giving a view of the motion of the atoms.

12. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 12 MacroModel http://www.schrodinger.com MacroModel supports a wide range of conformational searching methods, capable of handling systems ranging from small molecules to entire proteins. Maestro is the unified interface for all Schrödinger software.

13. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 13 MacroModel http://www.schrodinger.com Remote MacroModel jobs run on a different host from the one on which the command is entered to start the job. Distributed MacroModel allows certain types of calculations to be run in a distributed fashion across a number of different hosts. Schrödinger’s Job Control facility controls both remote and distributed MacroModel jobs. The Job Control facility enables remote and distributed MacroModel jobs to run reliably on a wide range of computer platforms. To run jobs on various hosts it’s necessary to set up the hosts for remote access and provide information on the hosts to the Job Control facility through a file named schrodinger.hosts.

14. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 14 MacroModel http://www.schrodinger.com Jobs can only be submitted to remote UNIX or LINUX hosts, except for jobs submitted to a grid computing server that includes Windows machines on the Grid. The Job Control facility submits jobs to hosts using the hosts file, which is named schrodinger.hosts. To run Schrödinger products under a grid computing system, it’s necessary to include the appropriate keywords in the hosts file.

15. Palermo, Grid Tutorial per l'Universita' di Palermo, 12.12.2007 15 QXP Qxp (Colin McMartin, Thistlesoft, PO Box 227, Colebrook, CT 06021, USA) is a software useful to: Discover relevant protein - ligand interactions Optimize/refine ligands orientation in the crystal structure Explore the active site: virtual mutagenesis of residues to check their role in the catalytic mechanism Virtual screening of large data sets It’s possible to distribute Qxp jobs on several machines in order to speed the simulation time advantage for the virtual screening of many compounds.