1. Molecular Docking Using GOLD Tommi Suvitaival Seppo Virtanen S-114.2500 Basics for Biosystems of the Cell Fall 2006

2. What is molecular docking? How a flexible ligand binds to a protein Ligand –Small molecule compared to the protein Protein –A macromolecule –Might have an active site onto which the ligand attaches

3. Interactions between the cyclic urea inhibitor and HIV-1 protease

4. What is molecular docking? (2) Difficult to predict Parameters to be considered: –Hydrogen bonds, lipophilic properties, van der Waals interactions –Possible metal ions –Tensions of the ligand backbone  Conformation

5. GOLD ’Genetic Optimization for Ligand Docking’ Input: –Exact protein and ligand configurations in order to get good results –Demand for other programs specialized in molecular visualization

8. Genetic algorithm search method used to search the different binding modes of the ligands The binding mode has geometric and chemical components Docked ligands ranked by fitness score  Fitness functions

9. Several possible conformations depicted in one picture

10. Fitness functions For determining the rank between possible geometries Two choices: GoldScore or ChemScore –Different parameters used Calculations based on chemical and physical theories –Geometrical properties –Bonding affinities

11. Genetic algorithm Initially a population of conformations is generated Scoring algorithm evaluates the fitness of each conformation –conformation=chromosome Genetic operations occur –Crossing-over Fit members of the population crossover and replace the worst member of the population –Migration –Mutation

12. Individual with the best properties is the result Highest rank