Rational Drug Design : HIV Integrase

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

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.

de novo Ligand Design

de novo Ligand Design

de novo Ligand Design

de novo Ligand Design

de novo Ligand Design

de novo Ligand Design

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

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

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

Results

Results

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

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

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

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

Site Mutations and Drug Resistance

Problem with Protein Flexibility http://folding.stanford.edu/villin/S300x300.105.56.95.mpg