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US 9,081,736 B2Granted
Modeling of mPGES-1 three-dimensional structures: applications in drug design and discovery
AssigneeUniversity of Kentucky Research Foundation
InventorsChang-Guo Zhan, Xiaoqin Huang, Adel Hamza
Life of this patent
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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.
Claims26
A method of structure-based identification of candidate compounds for regulation of interactions of mPGES-1 with its cognate ligands, comprising:
- a) providing, by a processor, a three dimensional structural representation of a mPGES-1 trimer and PGH2 and/or GSH wherein PGH2 interacts with GSH through hydrogen bonding between the peroxy group of PGH2 and the —SH group of GSH and wherein:
- i) each monomer of the trimer comprises 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) the trimer comprises a C3-fold symmetry;
- and
- iii) the representation of the trimer comprises a homology model based on the crystallographic structure of subunit 1 of cytochrome c oxidase;
- and
- b) identifying, by a processor, at least one candidate compound that interacts with the three dimensional structural representation of a) wherein said candidate has complementarity with at least one of the amino acid residues Q36, R110, T114, Y130, and Q134, and
- c) synthesizing the at least one candidate compound and determining the activity of the at least one candidate compound on m-PGES1 in vitro or in vivo.
13 more elements
A method of structure-based identification of candidate compounds for regulation of interactions of mPGES-1 with its cognate ligands, comprising:
- a) providing, by a processor, a three dimensional structural representation of a mPGES-1 substrate binding domain (SBD) and PGH2 and/or GSH, wherein PGH2 interacts with GSH through hydrogen bonding between the peroxy group of PGH2 and the —SH group of GSH and, 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 (AG) 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;
- and
- b) identifying, by a processor, at least one candidate compound that interacts with the three dimensional structural representation of a) wherein said candidate has complementarity with at least one of the amino acid residues Q36, R110, T114, Y130, and Q134, and
- c) synthesizing the at least one candidate compound and determining the activity of the at least one candidate compound on m-PGES1 in vitro or in vivo.
8 more elements
Dependencies are inferred from the claim text.