6C7I

Crystal structure of human phosphodiesterase 2A with 1-(2-chloro-5-methoxy-phenyl)-N-isobutyl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide

Summary for 6C7I

• Entry DOI: 10.2210/pdb6c7i/pdb
• Descriptor: cGMP-dependent 3',5'-cyclic phosphodiesterase, 1-(2-chloro-5-methoxyphenyl)-4-methyl-N-(2-methylpropyl)[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 161693.73

Authors

Xu, R.,Aertgeerts, K. (deposition date: 2018-01-22, release date: 2018-08-15, Last modification date: 2024-03-13)

Primary citation

Gomez, L.,Xu, R.,Sinko, W.,Selfridge, B.,Vernier, W.,Ly, K.,Truong, R.,Metz, M.,Marrone, T.,Sebring, K.,Yan, Y.,Appleton, B.,Aertgeerts, K.,Massari, M.E.,Breitenbucher, J.G.
Mathematical and Structural Characterization of Strong Nonadditive Structure-Activity Relationship Caused by Protein Conformational Changes.
J. Med. Chem., 61:7754-7766, 2018

PubMed Abstract: In medicinal chemistry, accurate prediction of additivity-based structure-activity relationship (SAR) analysis rests on three assumptions: (1) a consistent binding pose of the central scaffold, (2) no interaction between the R group substituents, and (3) a relatively rigid binding pocket in which the R group substituents act independently. Previously, examples of nonadditive SAR have been documented in systems that deviate from the first two assumptions. Local protein structural change upon ligand binding, through induced fit or conformational selection, although a well-known phenomenon that invalidates the third assumption, has not been linked to nonadditive SAR conclusively. Here, for the first time, we present clear structural evidence that the formation of a hydrophobic pocket upon ligand binding in PDE2 catalytic site reduces the size of another distinct subpocket and contributes to strong nonadditive SAR between two otherwise distant R groups.

PubMed: 30070482
DOI: 10.1021/acs.jmedchem.8b00713

Experimental method

X-RAY DIFFRACTION (1.713 Å)