Fragment- and negative image-based screening of phosphodiesterase 10A inhibitors.

Autor: Jokinen EM; Institute of Biomedicine, University of Turku, Turku, Finland., Postila PA; Department of Biological and Environmental Science, University of Jyvaskyla, Jyvaskyla, Finland., Ahinko M; Department of Biological and Environmental Science, University of Jyvaskyla, Jyvaskyla, Finland., Niinivehmas S; Institute of Biomedicine, University of Turku, Turku, Finland., Pentikäinen OT; Institute of Biomedicine, University of Turku, Turku, Finland.; Department of Biological and Environmental Science, University of Jyvaskyla, Jyvaskyla, Finland.; Aurlide Ltd., Lieto, Finland.
Jazyk: angličtina
Zdroj: Chemical biology & drug design [Chem Biol Drug Des] 2019 Oct; Vol. 94 (4), pp. 1799-1812. Date of Electronic Publication: 2019 Jul 19.
DOI: 10.1111/cbdd.13584
Abstrakt: 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 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.
(© 2019 John Wiley & Sons A/S.)
Databáze: MEDLINE
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