A1 Journal article (refereed)
Fragment‐ and Negative Image‐Based Screening of Phosphodiesterase 10A Inhibitors (2019)

Jokinen, E. M., Postila, P. A., Ahinko, M., Niinivehmas, S., & Pentikäinen, O. T. (2019). Fragment‐ and Negative Image‐Based Screening of Phosphodiesterase 10A Inhibitors. Chemical Biology and Drug Design, 94(4), 1799-1812. https://doi.org/10.1111/cbdd.13584

JYU authors or editors

Publication details

All authors or editors: Jokinen, Elmeri M.; Postila, Pekka A.; Ahinko, Mira; Niinivehmas, Sanna; Pentikäinen, Olli T.

Journal or series: Chemical Biology and Drug Design

ISSN: 1747-0277

eISSN: 1747-0285

Publication year: 2019

Volume: 94

Issue number: 4

Pages range: 1799-1812

Publisher: Wiley-Blackwell Publishing, Inc.

Publication country: United States

Publication language: English

DOI: https://doi.org/10.1111/cbdd.13584

Publication open access: Not open

Publication channel open access: 

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/65279

Abstract

A novel virtual screening methodology called fragment‐ and negative image‐based (F‐NiB) screening is introduced and tested experimentally using phosphodiesterase 10A (PDE10A) as a case study. Potent PDE10A‐specific small‐molecule inhibitors are actively sought after for their antipsychotic and neuroprotective effects. The F‐NiB combines features from both fragment‐based drug discovery and negative image‐based (NIB) screening methodologies to facilitate rational drug discovery. The selected structural parts of protein‐bound ligand(s) are seamlessly combined with the negative image of the target's ligand‐binding cavity. This cavity‐ and fragment‐based hybrid model, namely its shape and electrostatics, is used directly in the rigid docking of ab initio generated ligand 3D conformers. In total, 14 compounds were acquired using the F‐NiB methodology, 3D quantitative structure‐activity relationship modeling and pharmacophore modeling. Three of the small‐molecules inhibited PDE10A at ~27 μM to ~67 μM range in a radiometric assay. In a larger context, the study shows that the F‐NiB provides a flexible way to incorporate small‐molecule fragments into the drug discovery.

Keywords: Huntington's disease; Parkinson's disease; schizophrenia; screening analysis; medicines

Free keywords: phosphodiesterase 10A (PDE10A); schizophrenia; Parkinson’s disease; Huntington’s disease; negative image based (NIB); fragment; negative image based (FNiB) screening; virtual screening; structure-based virtual screening; radiometric activity assay; fragment-based drug discovery

Contributing organizations

Ministry reporting: Yes

Reporting Year: 2019

JUFO rating: 1