Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors. Issue 1 (1st January 2016)

• Record Type: Journal Article
• Authors: Varnes, Jeffrey G.; Geschwindner, Stefan; Holmquist, Christopher R.; Forst, Janet; Wang, Xia; Dekker, Niek; Scott, Clay W.; Tian, Gaochao; Wood, Michael W.; Albert, Jeffrey S.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 1(2016)
• Page Start: 197
• Page End: 202
• Publication Date: 2016-01-01
• Subjects: PDE10A -- Fragment-based drug discovery -- Fragment-assisted drug discovery -- Phosphodiesterase inhibitor -- Schizophrenia; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.10.100
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 ∼500 μM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4 μM hit, which, after preparation of a small number of analogs, was elaborated into a 16 nM 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.