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

Trypsinogen Trypsin Chymotrypsinogen Chymotrypsin Duodenal Cell Enterokinase

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

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

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

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

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

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

Scoring Translation, Rotation Least RMSD score

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

Simple 3D Superposition and Alignment

Modified Algorithm

Modified for Drug Docking

Biotin Docking to Streptavidin

Questions?