Modeling of mPGES-1 three-dimensional structures: applications in drug design and discovery

A method of structure-based identification of candidate compounds for regulation of interactions of mPGES-1 with its cognate ligands, comprising:

• a) providing a three dimensional structural representation of mPGES1 selected from the group consisting of:
• i) a three dimensional structural representation of a mPGES-1 substrate binding domain (SBD) wherein:
• a) amino acid residues Q36, R110, T114, Y130, and Q134 of mPGES-1 are associated with the prostaglandin H2 (PGH2)-binding site of the SBD;
• b) amino acid residue Y130 of mPGES-1 is associated with the peroxy head of PGH2 when PGH2 occupies at least a portion of the binding site;
• c) amino acid residue Y130 of mPGES-1 is associated with the —SH group of glutathione (GSH) when GSH occupies at least a portion of the binding site;
• d) amino acid residues R110, T114, and Q36 of mPGES-1 are associated with the carboxyl tail of PGH2;
• e) the calculated binding free energy (ΔG) for an SBD-PGH2 complex is between −5.0 kcal/mol and −9.0 kcal/mol;
• and
• f) the calculated binding free energy (ΔG) for an SBD-GSH complex is between −4.0 kcal/mol and −8.0 kcal/mol;
• and
• ii) a three dimensional structural representation of a mPGES-1 trimer wherein:
• a) each monomer of the trimer comprises the three-dimensional structural representation of the mPGES1 (SBD);
• b) the trimer comprises a C3-fold symmetry;
• and
• c) the representation of the trimer comprises a homology model based on the crystallographic structure of subunit 1 of cytochrome c oxidase;
• and
• b) identifying at least one candidate compound that interacts with the three dimensional structural representation of a).