A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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-tekijät tai -toimittajat
Julkaisun tiedot
Julkaisun kaikki tekijät tai toimittajat: Jokinen, Elmeri M.; Postila, Pekka A.; Ahinko, Mira; Niinivehmas, Sanna; Pentikäinen, Olli T.
Lehti tai sarja: Chemical Biology and Drug Design
ISSN: 1747-0277
eISSN: 1747-0285
Julkaisuvuosi: 2019
Volyymi: 94
Lehden numero: 4
Artikkelin sivunumerot: 1799-1812
Kustantaja: Wiley-Blackwell Publishing, Inc.
Julkaisumaa: Yhdysvallat (USA)
Julkaisun kieli: englanti
DOI: https://doi.org/10.1111/cbdd.13584
Julkaisun avoin saatavuus: Ei avoin
Julkaisukanavan avoin saatavuus:
Julkaisu on rinnakkaistallennettu (JYX): https://jyx.jyu.fi/handle/123456789/65279
Tiivistelmä
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.
YSO-asiasanat: Huntingtonin tauti; Parkinsonin tauti; skitsofrenia; seulonta; lääkkeet
Vapaat asiasanat: skitsofrenia; Parkinsonin tauti; Huntingtonin tauti; lääkkeet
Liittyvät organisaatiot
OKM-raportointi: Kyllä
Raportointivuosi: 2019
JUFO-taso: 1