Identification of dual inhibitor of phosphodiesterase 1B/10A using structure-based drug design approach
Document Type
Article
Publication Date
11-15-2021
Abstract
Schizophrenia is a neuropsychiatric disorder characterised by positive symptoms, negative symptoms, and cognitive impairment. Dopamine system dysfunction is strongly implicated in the aetiology of schizophrenia, where the hyperactivity in striatal dopamine and hypoactivity in cortical dopamine is considered the key feature of this serious mental disorder. Recent research has been directed toward finding new therapeutic agents to potentiate the D-1-receptor signalling and inhibit the D-2-receptor signalling. Two enzymes in the phosphodiesterase (PDE) family, PDE1B and PDE10A, have become desirable drug targets for psychiatric disorders in general and schizophrenia in particular due to their high expression in brain regions involved in schizophrenia. The PDE1B enzyme represents the major inactivation mechanism of D-1-receptors; therefore, the inhibition of PDE1B activity will potentiate the D-1-receptor signalling and mitigate the negative symptoms and cognitive impairments. Whereas the inhibition of PDE10A activity has generated much excitement as a potentially novel mechanism to treat the positive symptoms of schizophrenia, which are attributed to the increased dopamine D-2-receptor signalling. In which the inhibition of PDE10A activity will block the D-2-receptor signalling and improve the positive symptoms. Therefore, in the quest of searching for a new treatment for schizophrenia, we report here the identification of a novel inhibitor with dual action on PDE1B and PDE10A. A sequential pharmacophore-based virtual screening, molecular docking and molecular dynamic simulations; were combined to identify the new inhibitor. After a detailed analysis of the results, two ligands were selected for the biological evaluation, in which one of the two ligands showed significant inhibitory activity against both PDE1B and PDE10A. The newly identified inhibitor can be explored for further optimisation and evaluated in vivo for its antipsychotic-like effects. (C) 2021 Elsevier B.V. All rights reserved.
Keywords
Schizophrenia, PDE1B and PDE10A, Pharmacophore-based virtual screening, Molecular docking, Molecular dynamics simulations, Biological evaluation
Divisions
CHEMISTRY
Funders
Centre of Excellence in Research, Value Innovation and Entrepreneurship (CERVIE), UCSI University, Kuala Lumpur, Malaysia [Proj-2019In-FPS-018],UCSI University Trust Graduate Scholarship
Publication Title
Journal of Molecular Liquids
Volume
342
Publisher
Elsevier
Publisher Location
RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS