1. Rational Drug Design : HIV Integrase

2. A process for drug design which bases the design of the drug upon the structure of its protein target.
Structural mapping of the receptor (protein, P) active site
Identification of ligands (L) of complementary shape and appropriate functionality
Docking
4. Scoring

4. The catalytic domainhas an RNaseH-type fold and belongs to the superfamily of polynucleotidyl transferases. The active site is comprised of two Asp residues and one Glu, in the typicalD,D(35)E motif, each of which is required for catalysis.

5. de novo Ligand Design

6. de novo Ligand Design

7. de novo Ligand Design

8. de novo Ligand Design

9. de novo Ligand Design

10. de novo Ligand Design

11. four criteria to conclude that integrase is theinhibitor target:
1. found to be active against recombinant integrase.
2. infected cells treated with the drug must show an accumulation of 2-LTR circles, resulting from the accumulation of viral cDNA and decreased HIV integration into host
3. integrase mutations must be found in drug-resistant viruses
4, the drug should be inactive in biochemical assays against recombinantintegrases bearing the mutations identified in the drug-resistant viruses
DKAs
DCQ acids; DCT acids
PDP
SQL
Quinolone
derived

12. Issues Crystal structure available for Integrase but :
I. Limitations of crystal structure:
only catalytic domain
DNA binding not revealed
cystal structure vs. physiologically active structure
II. Position of hydrogens undetermined
III. Residues missing or ill-defined
IV. Protonation of His undetermined
V. Solvation

13. Issues
Crystal structure available for Integrase Catalytic Domain but :
I. Crystal reveals trimeric structure
II. Position of hydrogens undetermined
III. Residues missing or ill-defined
IV. Protonation of His undetermined
V. Solvation

14. Results

15. Results

16. Ligand Design Criterion for Ligand Selection:
I. Theoretical and experimental structures
II. Fill active site
III. Conformational structures

17. Ligand Design Criterion for Ligand Selection:
I. Theoretical and experimental structures
II. Fill active site
III. Conformational structures

18. Ligand Design Criterion for Ligand Selection:
I. Theoretical and experimental structures
II. Fill active site
III. Conformational structures

19. Site Mutations and Drug Resistance
The prediction of the affects of mutations within the
binding site on the effects of the ligands involves:
I. Identifying possible sights of mutations
II. Determining effect of mutations

20. Site Mutations and Drug Resistance

21. Problem with Protein Flexibility