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US 2008/0177521 A1Published application
Modeling of mPGES-1 three-dimensional structures: applications in drug design and discovery
AssigneeUniversity of Kentucky
InventorsChang-Guo Zhan, Xiaoqin Huang, Adel Hamza
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Abstract
This invention relates to representations of prostaglandin synthase three-dimensional structures. Such representations are suitable for designing agents that modulate the activity of the enzyme by binding to the substrate binding domain.
Claims31
A method of identifying a set of candidate structures of a polypeptide, the method comprising:
- a) obtaining a first amino acid sequence derived from a query polypeptide;
- b) obtaining a second amino acid sequence derived from a template polypeptide, wherein the second sequence comprises:
- i) a predetermined three-dimensional structure;
- and
- ii) at least 50% sequence homology with the first sequence;
- c) performing a sequence alignment between the first sequence and the second sequence, and identifying common secondary structures;
- d) generating a plurality of candidate topological structures by applying predetermined geometric parameters to the secondary structures of c) and transforming each topological structure in to the amino acid residues associated with the secondary structures;
- e) generating a first conformation set by screening the plurality of candidate topological structures of d) with the predetermined geometric parameters and identifying the structures that correspond to the parameters;
- f) generating a second conformation set by applying energy minimization functions to the first conformation set and identifying energetically-favored conformations;
- and
- g) generating a final conformation set by selecting those structures that exhibit an energy gradient having a root mean square deviation (RMSD) of less than 0.001 kcal mol−1 Å−1, wherein the final conformation set represents the set of candidate structures of the query polypeptide.
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A representation of a three-dimensional structure of the mPGES-1 substrate binding domain (SBD) characterized in that:
- a) amino acid residues Q36, R110, T114, Y130, and Q134 of mPGES-1 are associated with the PGH2-binding site of the SBD;
- b) amino acid residue Y130 of mPGES-1 is associated with the peroxy head of prostaglandin H2 (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 (AG) for an SBD-GSH complex is between −4.0 kcal/mol and −8.0 kcal/mol.
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Dependencies are inferred from the claim text.