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- Title
Combining Pharmacophore-Based Screening And Molecular Dynamics Simulations In The Identification Of Novel Inhibitor With Dual Action On PDE1B And PDE10A.
- Authors
Al-Nema, Mayasah; Gaurav, Anand; Lee, Vannajan Sanghiran; Gunasekaran, Baskaran; Lee, Ming Tatt; Okechukwu, Patrick
- Abstract
Introduction: The inhibition of Phosphodiesterase 1B (PDE1B) has been proposed as a novel way to improve the cognitive function in many neurodegenerative and neuropsychiatric diseases, while; the inhibition of PDE10A has been proposed to alleviate the symptoms in Huntington’s disease and Schizophrenia. Therefore, the present study aims to identify a dual PDE1B/PDE10A inhibitor as a potential drug candidate for the treatment of the cognitive symptoms of schizophrenia along with the positive and negative symptoms. Methods: A structure-based pharmacophore model for PDE1B and PDE10A was generated and validated using the test set and the decoy set method. The validated pharmacophore models were used as 3D queries in the virtual screening of Zinc database. The retrieved hits were filtered based on Lipinski’s rule of 5, pharmacophore fit score, and the binding affinity for PDE1B and PDE10A. The stability of the ligands within the active site of the target proteins was studied using molecular dynamics simulations. Results: Zinc41306568 from Zinc database exhibited the highest affinity for PDE1B and PDE10A. The modelling studies demonstrated that Zinc41306568 interacted with the hydrophobic residues TYR74 and ILE223 and the P-clamp residues, LEU240, PHE244 and PHE276 in PDE1B. While in PDE10A, Zinc41306568 involved in hydrophobic interactions with LEU189, VAL232, ALA243, TYR247 and MET267, besides the common interactions with the P-clamp residues ILE246, PHE250 and PHE283. Conclusion: Dual inhibitors of PDE1B and PDE10A have not been reported in the literature; therefore, Zinc41306568 is considered the first dual inhibitor of PDE1B and PDE10A that has been identified by applying a computer-aided drug discovery approach. The newly identified inhibitor will be explored for further optimisation and evaluated in vivo for its antipsychotic-like effects.
- Subjects
MOLECULAR dynamics; HUNTINGTON disease; HYDROPHOBIC interactions; COGNITIVE ability; NEURODEGENERATION
- Publication
Malaysian Journal of Medicine & Health Sciences, 2022, Vol 18, p59
- ISSN
1675-8544
- Publication type
Article