Methods for designing, selecting and/or optimizing allosteric processing inhibitors for matrix metalloproteinases

A method for evaluating the ability of a chemical entity to associate with all or part of an allosteric binding site of proMMP9 comprising the steps of:

• a. employing the structural coordinates of proMMP9 according to any to any one of Tables 11-14 to generate a three-dimensional model of said proMMP9 on a computer, wherein said computer comprises the means for generating said three-dimensional model;
• b. identifying three-dimensional structural information of an allosteric binding site for said chemical entity, wherein said allosteric binding site comprises amino acid residues 100-102, 110, 114, 177-179, 190-193, and 405-410, and wherein said binding site comprises a region of space that is occupied by Phe 107 in the apo form of proMMP9, numbering taken from full-length human matrix metalloproteinase-9 precursor, proMMP9(1-707) (SEQ ID NO:1);
• c. employing computational means to perform a fitting operation between the chemical entity and said three-dimensional structural information of all or part of the allosteric binding site identified in (b);
• and
• d. analyzing the results of said fitting operation to quantitate the association between the chemical entity and all or part of the allosteric binding site.

A method of employing a computer for evaluating the ability of a chemical entity to associate with all or part of an allosteric binding site of proMMP9, wherein said computer comprises a machine-readable data storage medium comprising a data storage material encoded with the structure coordinates of said proMMP9 according to any one of Tables 11-14 and means for generating a three-dimensional graphical representation of said proMMP9, and wherein said method comprises the steps of:

• a. employing the structural coordinates of said proMMP9 according to any one of Tables 11-14 to generate a three-dimensional model of said proMMP9 on said computer;
• b. identifying three-dimensional structural information of an allosteric binding site for said chemical entity, wherein said allosteric binding site comprises amino acid residues 100-102, 110, 114, 177-179, 190-193, and 405-410, and wherein said binding site comprises a region of space that is occupied by Phe 107 in the apo form of proMMP9;
• c. employing computational means to perform a fitting operation between the chemical entity and said three-dimensional structural information of all or part of the allosteric binding site identified in (b);
• and
• d. analyzing the results of said fitting operation to quantitate the association between said chemical entity and said three-dimensional structural information of all or part of the allosteric binding site.