Fragment- and negative image-based screening of phosphodiesterase 10A inhibitors.
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.
['Jokinen|Elmeri M|EM|0000-0003-2352-6550', 'Postila|Pekka A|PA|', 'Ahinko|Mira|M|', 'Niinivehmas|Sanna|S|', 'Pentikäinen|Olli T|OT|0000-0001-7188-4016']
D004353:Drug Evaluation, Preclinical D006801:Humans D062105:Molecular Docking Simulation D010726:Phosphodiesterase Inhibitors D010727:Phosphoric Diester Hydrolases
negative image-based phosphodiesterase 10A virtual screening fragment- and negative image-based (F-NiB) screening fragment-based drug discovery Huntington's disease Parkinson's disease radiometric activity assay schizophrenia structure-based virtual screening