4. Lead Discovery Strategies Low High Knowledge Base Random Screening Targeted Screening Database Mining High Low Compound Diversity Array Synthesis Diverse Arrays Targeted Arrays
5. NR Chemistry Strategy Array Design molecular descriptors “ NR space” Array Synthesis NR targeted arrays NR compound sets Array Screening screening data virtual screening combichem
6. NR Array Design Universe of Compounds (Virtual or Real) Nuclear Receptor Ligands Chemistries Universe of Compounds (Virtual or Real) NR Ligands Chemistries
7. Defining NR Chemical Space DiverseSolutions (DVS) Select Descriptors for a Descriptor Space such that: 1) Maximize dimensionality 2) Minimize axes correlation 3) Separate WDI and NR900 NR900 WDI (42,608 cmpds) WDI (42,608 cmpds) NR900 Apply Basis Set of Descriptors 52 Standard 2D and 3D BCUT Metrics SAVOL Molecular Volume 5 Descriptors measure: 1) Charge 2) Polarizability 3) Molecular Shape 4) Molecular Size
8. NR Chemical Space NR Chemical Space Training set 900 NR ligands 50 pseudo-3D descriptors Liquid Stores (600k compounds) 70k compounds (E = 12%) Virtual Screen Size Shape (2) Charge Polarizability E = % of compounds in NR space GSK Data World Drug Index Literature
9. Measures of Array Profiles 0% Virtual Effectiveness for Target Space Poor Coverage in Target Space ~40% Virtual Effectiveness for Target Space Good Coverage in Target Space Collection A Target Space Target Space Descriptor Axis 1 Descriptor Axis 2 Collection B Target Space Target Space Descriptor Axis 1 Descriptor Axis 2
33. Workflow for ROCS Analysis of AR Ligands Virtual Array (SMILES) DHT Shape Query CONCORD for 3D coords OMEGA for Conformers Shape Score Shape Match ROCS for Shape Match
35. Strategy for Virtual High-throughput Docking Large Virtual Array ... Virtual Compounds to be Docked Virtual Compounds to be Synthesized M1 Monomers M2 Monomers M3 Monomers Mx Monomers Enumeration Enumeration Pharmacophore Analysis ROCS Analysis Generation of Conformer Ensemble Dock into Protein Active Site Descriptor Evaluation and Virtual Screening Selection
40. Acknowledgements Pete Kitrinos Bob Johnson Dean Phelps Melissa Gomez Matt Lochansky Christina Sheedy David Gray Rosemary Sasse Matilde Caivano Vicky Strzelczyk Margaret Clackers Jennifer Brown Ryan Trump Phil Turnbull J.B. Blanc Graham Robinett Peter Brown Bob Wiethe Bill Stuart David Drewry David Jones Andy Noe Bill Hoekstra Tim Willson Frank Schoenen Dudley Rose Donald Lyerly James Ballinger Joyce Turner Brenda Ray Eugene Stewart Mill Lambert Aaron Miller