1. Drug Docking Computer Science Department Brigham Young University Andrew Harris Mark Clement Kenneth Sundberg

2. Trypsinogen Trypsin Chymotrypsinogen Chymotrypsin Duodenal Cell Enterokinase

3. Genetic Disease Some diseases caused by over- expression/under-expression of certain proteins or enzymes in a given pathway Some diseases caused by over- expression/under-expression of certain proteins or enzymes in a given pathway Down Syndrome – Trisomy 21, extra 21 st chromosome Down Syndrome – Trisomy 21, extra 21 st chromosome Larger oral-pharyngeal anatomy Larger oral-pharyngeal anatomy Smaller jaw Smaller jaw Learning disability Learning disability Theoretically treatable with drugs Theoretically treatable with drugs

4. Drug Design Process 1. Find Targets, Inhibitors, Compounds 2. Experiment Drug Candidates 3. Validate in vitro

5. Information ZINC, Human Genome Project now make this sequence information available ZINC, Human Genome Project now make this sequence information available Reduce time sifting through, predict side effects Reduce time sifting through, predict side effects

6. PyMOL A molecular graphics visualization tool A molecular graphics visualization tool Embedded Python interpreter Embedded Python interpreter Open Source Open Source

7. Drug Docking Algorithm Searching Searching Superposition Superposition Rotation Rotation Scoring Scoring Root Mean Square Deviation (RMSD) Root Mean Square Deviation (RMSD) Bond Energies Bond Energies

8. Searching Centroid Calculation, Geometric Translation Centroid Calculation, Geometric Translation Matrix Multiplication Rotation Matrix Multiplication Rotation

9. Scoring Translation, Rotation Least RMSD score

10. Drug Docking Algorithm transpose centroids to the origin transpose centroids to the origin foreach angular displacement in x foreach angular displacement in x foreach angular displacement in y foreach angular displacement in y foreach angular displacement in z foreach angular displacement in z Calculate RMSD Calculate RMSD If this RMSD is less than current minimum, save it If this RMSD is less than current minimum, save it

11. Simple 3D Superposition and Alignment

12. Modified Algorithm

13. Modified for Drug Docking

14. Biotin Docking to Streptavidin

15. Questions?