Understanding microscopic binding of human microsomal prostaglandin E synthase-1 with substrates and inhibitors by molecular modeling and dynamics simulation.
Microsomal prostaglandin E synthase-1 (mPGES-1) is a promising target for development of next-generation anti-inflammatory drugs. It is crucial for rational design of the next-generation anti-inflammatory drugs to know the three-dimensional (3D) structure of mPGES-1 trimer and to understand how mPGES-1 binds with substrates and inhibitors. In the current work, a 3D structural model of human mPGES-1 trimer has been developed, for the first time, by performing combined homology modeling, molecular docking, and molecular dynamics simulation. The 3D structural model enables us to understand how mPGES-1 binds with its substrates/inhibitors, and the key amino acid residues for the mPGES-1 binding with ligands have been identified. The detailed 3D structures and calculated binding free energies for mPGES-1's binding with substrates and inhibitors are all consistent with available experimental data, suggesting that the 3D model of the mPGES-1 trimer and the enzyme-ligand binding modes are reasonable. The new structural insights obtained from this study should be valuable for rational design of next-generation anti-inflammatory drugs.
Hamza
Adel
A
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536, USA.
Abdulhameed
Mohamed Diwan M
MD
Zhan
Chang-Guo
CG
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D005982:Glutathione Transferase / Q000737:chemistry; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D044262:Prostaglandin H2 / Q000737:chemistry* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
D004791:Enzyme Inhibitors; D044262:Prostaglandin H2; C122107:microsomal glutathione S-transferase-I; D005982:Glutathione Transferase; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D005978:Glutathione