Al-Nema, Mayasah and Gaurav, Anand and Lee, Vannajan Sanghiran and Gunasekaran, Baskaran and Lee, Ming Tatt and Okechukwu, Patrick (2021) Identification of dual inhibitor of phosphodiesterase 1B/10A using structure-based drug design approach. Journal of Molecular Liquids, 342. ISSN 0167-7322, DOI https://doi.org/10.1016/j.molliq.2021.117485.
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| 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 |
| Uncontrolled Keywords: | Schizophrenia; PDE1B and PDE10A; Pharmacophore-based virtual screening; Molecular docking; Molecular dynamics simulations; Biological evaluation |
| Subjects: | Q Science > QC Physics Q Science > QD Chemistry |
| Divisions: | Faculty of Science > Department of Chemistry |
| Depositing User: | Ms Zaharah Ramly |
| Date Deposited: | 29 Jul 2022 08:30 |
| Last Modified: | 29 Jul 2022 08:30 |
| URI: | http://eprints.um.edu.my/id/eprint/28273 |
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