New Dual PDE1B and PDE10A Inhibitors Identified via Ligand-Based Pharmacophore Modelling and Virtual Screening

Abstract

Context Schizophrenia is a chronic neuropsychiatric disorder affecting over 1% of the world population. Current antipsychotic therapy shows inadequacy in mitigating the negative and cognitive symptoms, besides causing undesirable extrapyramidal side effects. Inhibition of PDE1B and PDE10A simultaneously can mitigate positive, negative, and cognitive symptoms. Thus, this study was aimed at identifying new dual PDE1B and PDE10A inhibitors using ligand-based pharmacophore modelling, virtual screening, and molecular docking. Pharmacophore models for PDE1B and PDE10A produced Gunner-Henry (GH) scores of 0.83 and 0.71, respectively. Pharmacophore model based virtual screening and molecular docking led to the identification of UNPD167314 as the lead compound with good binding affinity for PDE1B (-8.4 kcal/mol) and PDE10A (-9.7 kcal/mol). The binding interactions include hydrophobic interactions with P-clamp and hydrogen bonding with invariant glutamine. Structural modifications resulted in the design of 51 novel inhibitors, with compound 18 exhibiting the highest binding affinity for both PDE1B (-10.6 kcal/mol) and PDE10A (-11.7 kcal/mol) following substitution of tertbutyl at R1, hydroxyl at R2, and carboxyl at R3. Methods LigandScout 4.4.8 was used to generate, validate, and refine the ligand-based pharmacophore models for PDE1B and PDE10A, followed by sequential virtual screening of the Universal Natural Products Database. The hits were screened further using DruLiTo software to ensure BBB penetration. Pan Assay Interference Compounds were removed using PAINS-Remover server. SwissADME and PreADMET were used to deduce pharmacokinetic parameters of the screened compounds. Finally, Molecular docking and visualization of the dual hits were performed using Autodock Vina 1.2.0, followed by structural modifications to improve interaction affinity.

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson’s Disease through a Computational Approach

“…Hence, the crucial interactions responsible for inhibiting PDE10A activities involve a hydrophobic interaction with the residues that form the P-clamp. 34 Therefore, the residues of particular importance are Ile629, Phe696, and Gln726 34 (Figure 1).…”

“…Phe696 is one of the significant residues in the inhibition of PDE10A. 34 Among the top alkaloids in the library, Aurachin A represented the interaction with this particular residue (Figure 4B). However, the other residue, Phe729, was found in the interaction profiles of many alkaloids, namely, CJ-13536, Huajiaosimuline, 3-Prenyl-4-prenyloxyquinolin-2-one, and Isaindigotone.…”

“…The permissible limit of flexibility is less than 10 rotatable bonds, in accordance with Lipinski's rule of five (RO5) for CNS-active drugs. Quinolines 2,3,5,6,8,9,14,16,25,27,29,34,39,40,and 42 did not meet this criterion. Other than these compounds, all quinolines and quinazolines reside within the admissible limit of molecular flexibility.…”