4MRW: Crystal structure of PDE10A2 with fragment ZT0120 (7-chloroquinolin-4-ol)

Fragment-based lead discovery (FBLD) is a technique in which small, low-complexity chemical fragments of 6 to 15 heavy atoms are screened for binding to or inhibiting activity of the target. Hits are then linked and/or elaborated into tightly binding ligands, ideally yielding early lead compounds for drug discovery. Calorimetry provides a label-free method to assay binding and enzymatic activity that is unaffected by the spectroscopic properties of the sample. Conventional microcalorimetry is hampered by requiring large quantities of reagents and long measurement times. Nanocalorimeters can overcome these limitations of conventional isothermal titration calorimetry. Here we use enthalpy arrays, which are arrays of nanocalorimeters, to perform an enzyme activity-based fragment screen for competitive inhibitors of phosphodiesterase 10A (PDE10A). Two dozen fragments with KI <2 mM were identified and moved to crystal soaking trials. All soak experiments yielded high-resolution diffraction, with two-thirds of the fragments yielding high-resolution co-crystal structures with PDE10A. The structural information was used to elaborate fragment hits, yielding leads with KI <1 microM. This study shows how array calorimetry can be used as a prescreening method for fragment-based lead discovery with enzyme targets and paired successfully with an X-ray crystallography secondary screen.
PDB ID: 4MRWDownload
MMDB ID: 119394
PDB Deposition Date: 2013/9/17
Updated in MMDB: 2014/05
Experimental Method:
x-ray diffraction
Resolution: 1.96  Å
Source Organism:
Similar Structures:
Biological Unit for 4MRW: monomeric; determined by author and by software (PISA)
Molecular Components in 4MRW
Label Count Molecule
Protein (1 molecule)
Camp and Camp-inhibited Cgmp 3',5'-cyclic Phosphodiesterase 10A(Gene symbol: PDE10A)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB