Use of computationally derived protein structures of genetic polymorphisms in pharmacogenomics for drug design and clinical applications

A computer-based method of selecting a drug therapy for subjects based on genetic polymorphisms, comprising:

• determining an amino acid sequence of at least two polymorphic variants of a target protein wherein said sequences include the polymorphic site;
• generating a 3-D protein structural variant model for each of said polymorphic variants using said sequences and one or more methods selected from the group consisting of X-ray crystallography, NMR, searching a protein structure database, homology modeling, de novo protein folding, and computational protein structure prediction;
• computationally docking a drug molecule with the target protein models;
• energetically refining the docked complexes;
• determining the binding interactions between the drug or other drug candidate molecules and the models;
• and
• selecting a drug therapy based on the drug or drugs that have the most favorable binding interactions with the structural variant models.

A computer-based method of selecting a drug therapy for subjects based on genetic polymorphisms, comprising:

• computationally docking a drug molecule with a 3-D protein structural variant model of a target protein that is the product of a gene exhibiting genetic polymorphisms;
• energetically refining the docked complexe;
• determining the binding interactions between the drug or other drug candidate molecules and the model;
• and
• selecting a drug therapy based on the drug or drugs that have the most favorable binding interactions with the structural variant model;
• wherein said 3-D protein structural variant model is generated using an amino acid sequence of said target protein said sequence comprising the polymorphic site of said target protein, and one or more methods selected from the group consisting of X-ray crystallography, NMR, searching a protein structure database, homology modeling, de novo protein folding, and computational protein structure prediction.