Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors

Bioorg Med Chem Lett. 2016 Jan 1;26(1):197-202. doi: 10.1016/j.bmcl.2015.10.100. Epub 2015 Nov 11.

Abstract

Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selection and design but do not serve as starting points for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted in parallel against PDE10A where fragment hit co-crystallography was not available. The fragment screen led to prioritized fragment hits (IC50's ∼500μM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4μM hit, which, after preparation of a small number of analogs, was elaborated into a 16nM lead. This approach highlights the strength of FADD, as fragment methods were applied despite the absence of co-crystallographical information to efficiently identify a lead compound for further optimization.

Keywords: Fragment-assisted drug discovery; Fragment-based drug discovery; PDE10A; Phosphodiesterase inhibitor; Schizophrenia.

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical*
  • High-Throughput Screening Assays*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Phosphodiesterase Inhibitors / analysis*
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Structure-Activity Relationship

Substances

  • Phosphodiesterase Inhibitors
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases