3QPO

Structure of PDE10-inhibitor complex

Summary for 3QPO

• Entry DOI: 10.2210/pdb3qpo/pdb
• Related: 2O8H 2OVV 2OVY 3QPN 3QPP
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, SULFATE ION, ZINC ION, ... (6 entities in total)
• Functional Keywords: phosphodiesterase inhibitors, structure-based drug design, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Rattus norvegicus (brown rat,rat,rats)
• Cellular location: Cytoplasm: Q9QYJ6
• Total number of polymer chains: 1
• Total formula weight: 42384.09

Authors

Pandit, J.,Marr, E.S. (deposition date: 2011-02-14, release date: 2011-06-15, Last modification date: 2024-02-21)

Primary citation

Helal, C.J.,Kang, Z.,Hou, X.,Pandit, J.,Chappie, T.A.,Humphrey, J.M.,Marr, E.S.,Fennell, K.F.,Chenard, L.K.,Fox, C.,Schmidt, C.J.,Williams, R.D.,Chapin, D.S.,Siuciak, J.,Lebel, L.,Menniti, F.,Cianfrogna, J.,Fonseca, K.R.,Nelson, F.R.,O'Connor, R.,Macdougall, M.,McDowell, L.,Liras, S.
Use of Structure-Based Design to Discover a Potent, Selective, In Vivo Active Phosphodiesterase 10A Inhibitor Lead Series for the Treatment of Schizophrenia.
J.Med.Chem., 54:4536-4547, 2011

PubMed Abstract: Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.

PubMed: 21650160
DOI: 10.1021/jm2001508

Experimental method

X-RAY DIFFRACTION (1.8 Å)