Methods to Prepare and Employ Binding Site Models for Modulation of Phosphatase Activity and Selectivity Determination

A method to enrich a chemical library for a modulator of a tyrosine phosphatase enzyme comprising the following steps:

• using a computer algorithm to generate a binding model;
• preparing a 3-dimensional conformation database of candidate modulators;
• preparing a 3-dimensional representation of the target enzyme;
• generating 3-dimensional representations of modulation sites;
• determining the structure coordinates of the amino acid residues that constitute the binding sites;
• comparing said binding model to a candidate molecule;
• estimating the attraction, repulsion and steric hindrance of a potential ligand to the enrichment model;
• and
• selecting molecules that are compatible with the enrichment model.

A method of using a SHP1 or SHP2 enrichment model to identify ligands that bind to SHP1 or SHP2 and modulate its function, comprising the steps of

• generating one or more electronic representations of a compound or fragment;
• assembling an electronic representation or representations in an electronic database;
• positioning selected chemical entities in a variety of orientations inside an enrichment model;
• using selected chemical entities to perform a manual or computer-assisted fitting of said electronic representations and an enrichment model;
• analyzing the results of said fitting operation to quantify the association between said chemical entities and said enrichment model;
• evaluating the quality of the fitting of said chemical entities to said enrichment mode using a scoring function, shape complementarity, interaction energy estimate and visual inspection followed by energy minimization and molecular dynamics;
• and
• identifying suitable chemical entities and connecting same into a single compound in relation to said enrichment model.