Fragment‐ and Negative Image‐Based Screening of Phosphodiesterase 10A Inhibitors
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
Published inChemical Biology and Drug Design
© 2019 John Wiley & Sons A/S
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. ...
PublisherWiley-Blackwell Publishing, Inc.
skitsofrenia Parkinsonin tauti Huntingtonin tauti lääkkeet 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 seulonta
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Additional information about fundingThe project was funded by the Jenny and Antti Wihuri Foundation (MA), the Emil Aaltonen Foundation (MA), the Finnish Cultural Foundation, Varsinais‐Suomi Regional fund (EMJ; 85182232), and the Academy of Finland (SN; 315492). CSC, The Finnish IT Centre for Science, is acknowledged for generous computational grants (O.T.P. projects jyy2516, jyy2585, and jyy2586).
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