1. GRIDP: Web-enabled Drug Discovery Is there any way I can use computational tools to reduce the number of molecules I have to screen to a manageable number, like 100 or so, because even 100 is a stretch, and it’s not like I have a drug-company budget…

2. GOAL: Screen 100 find a hit.

3. Starting Point Collaborator Literature/Vendor Active Molecule PDB Your Lab Protein Structure 30% sequence identity Modbase, Modweb, Homology Model

4. Active Molecule

5. ShapeColorHits

6. Protein Structure (Homology) Refine Binding Site Dock Simulation (Energy)

7. Refine, Dock, Simulate Refine, Simulate (shared memory) –10K’s to 100K’s of atoms –QM/MM calc, QM treatment of ligand and QM or MM treatment of protein for more accurate charges. Dock (parallel) –Rigid: 5 M candidates, up to 400 conformations each, –10 60 potential drug-like molecules

8. Problem for Biologists/Chemists Refine Binding Site Dock Simulation (Energy)

9. Problem for Biologists/Chemists Execute Options -param : A parameter file Inputting Ligands -dbase : File of multiconformer ligands. -conftest : Set the test for detecting if sequential molecule records in the ligand database are conformers. -molnames : Tells FRED to only dock molecules with names specified in a text file -assign_ligand_charges : Assign AM1BCC charges to all input ligands. MASC Preparation -reference_receptors : Text file listing custom masc reference receptors files. -no_masc_data_calc : Don't calculate any masc data for this run -recalculate_masc_data : Force re-calculation of masc data on ligands with existing data -report_masc_failures : Report failure of ligands to dock to masc reference structures Receptor Site -rec : Receptor site file molecules will be docked into. -pharm : File of custom docking constraints -assign_protein_charges : Assign MMFF charges to receptor (otherwise accept input) Create Site -pro : Protein molecule to convert into a receptor site. -strip_water : Strip waters from the protein before creating the receptor. -bound_ligand : Known ligand bound to the protein. -box : A box defining the receptor site -addbox : Adjusts the box created with the -box flag by extending all sides by this value -no_inner_contour : Create the receptor without an inner contour.