1. Lead discovery (single snapshot from xray) –Forcefield-based enthalpy (fast) Energy (Coulomb, van der Waals) Solvation energy (Generalized-Born) Non-polar energy (Solvent-accessible surface area) –Empirical function for entropy calculations (fast) Lead optimization (multiple snapshots from MD simulation) –Forcefield-based enthalpy Energy (Coulomb, van der Waals) Solvation energy (Poisson-Boltzmann) Non-polar energy (SA) –Entropy using normal mode analysis (slow, but accurate) –Cheminformatics to generate multiple structures for free energy calculations Physics-based scoring

2. Grid implementation Globus toolkit Teragrid Infrastructure: 40 core cluster, multiple dual machines

3. A platform for empirical score development Three components needed –Three-dimensional structures PDB, MMDB –Binding constants PDBcal from Meroueh lab BindingDB (Gilson lab) MOAD (Carlson lab) PDBbind –Software for non-linear least squares analysis and building binding curves for validation of model

4. Applications Virtual screening against anticancer and anti-microbial targets –PDGF-R (brain cancer) –uPAR (breast cancer) –Sortase (bacterial virulence) –APE1 –PRL1 –TG2 (ovarian cancer) In vitro studies (SPR, ITC, biochemical assays) –Active compounds for uPAR –Active peptides for PDGF-R Cell-based assays