• 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

Grid implementation

• Globus toolkit • Teragrid• Infrastructure: 40 core cluster, multiple

dual machines

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

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