Identification of dual inhibitor of phosphodiesterase 1B/10A using structure-based drug design approach

Al-Nema, Mayasah; Gaurav, Anand; Lee, Vannajan Sanghiran; Gunasekaran, Baskaran; Lee, Ming Tatt; Okechukwu, Patrick Nwabueze

doi:10.1016/j.molliq.2021.117485

Cited by 8 publications

(8 citation statements)

References 65 publications

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“…We have reported previously the identification of a dual inhibitor of PDE1B and PDE10A, compound 2, that has shown a potent inhibitory activity in vitro assay using recombinant human enzymes [ 25 ]. Here in the current study, we have presented data validating the safety and antipsychotic-like activity of compound 2.…”

Section: Discussionmentioning

confidence: 99%

“…We recently identified a novel dual inhibitor of PDE1B and PDE10A, compound 2 [(3-fluorophenyl)(2-methyl-2,3-dihydro-4H-benzo[b][ 1 , 4 ]oxazin-4-yl)methanone] and confirmed the inhibitory activity for PDE1B and PDE10A in vitro ; the half-maximal inhibitory concentration was 0.85 μM and 1.34 μM for PDE1B and PDE10A, respectively [ 25 ]. In this study, we evaluated the safety profile of compound 2 and characterised the in vivo efficacy as a novel treatment of schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the acute oral toxicity and antipsychotic activity of a dual inhibitor of PDE1B and PDE10A in rat model of schizophrenia

et al. 2022

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Phosphodiesterase 1B (PDE1B) and PDE10A are dual-specificity PDEs that hydrolyse both cyclic adenosine monophosphate and cyclic guanosine monophosphate, and are highly expressed in the striatum. Several reports have suggested that PDE10A inhibitors may present a promising approach for the treatment of positive symptoms of schizophrenia, whereas PDE1B inhibitors may present a novel mechanism to modulate cognitive deficits. Previously, we have reported a novel dual inhibitor of PDE1B and PDE10A, compound 2 [(3-fluorophenyl)(2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone] which has shown inhibitory activity for human recombinant PDE1B and PDE10A in vitro. In the present study, the safety profile of compound 2 has been evaluated in rats in the acute oral toxicity study, as well as; the antipsychotic-like effects in the rat model of schizophrenia. Compound 2 was tolerated up to 1 g/kg when administered at a single oral dose. Additionally, compound 2 has strongly suppressed ketamine-induced hyperlocomotion, which presented a model for the positive symptoms of schizophrenia. It has also shown an ability to attenuate social isolation induced by chronic administration of ketamine and enhanced recognition memory of rats in the novel object recognition test. Altogether, our results suggest that compound 2 represents a promising therapy for the treatment of the three symptomatic domains of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of the acute oral toxicity and antipsychotic activity of a dual inhibitor of PDE1B and PDE10A in rat model of schizophrenia

et al. 2022

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“…After the simulation, we separately analyzed the root mean square deviation (RMSD) of the proteins and small molecules in each complex. 31 Anti-PVY Activity of Candidate Compounds in N. Benthamiana. N. benthamiana plants grew in a Guizhou University growth room at 26 °C under a 16/8 h light/dark cycle.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…To investigate the dynamic binding mode between proteins and small molecules, we simulated the molecular dynamics of each complex for 10 ns in the Amber program by using the ff19SB force field and the default values of the other parameters. After the simulation, we separately analyzed the root mean square deviation (RMSD) of the proteins and small molecules in each complex …”

Section: Materials and Methodsmentioning

confidence: 99%

Tryptanthrin Derivative B1 Binds Viral Genome-Linked Protein (VPg) of Potato Virus Y

Wu,

Zhang,

Huang

et al. 2024

J. Agric. Food Chem.

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Potato virus Y (PVY) is a plant virus that is known to be responsible for substantial economic losses in agriculture. Within the PVY genome, viral genome-linked protein (VPg) plays a pivotal role in the viral translation process. In this study, VPg was used as a potential target for analyzing the antiviral activity of tryptanthrin derivatives. In vitro, the dissociation constants of B1 with PVY VPg were 0.69 μmol/L (measured by microscale thermophoresis) and 4.01 μmol/L (measured via isothermal titration calorimetry). B1 also strongly bound to VPg proteins from three other Potyviruses. Moreover, in vivo experiments demonstrated that B1 effectively suppressed the expression of the PVY gene. Molecular docking experiments revealed that B1 formed a hydrogen bond with N121 and that no specific binding occurred between B1 and the PVY VPgN121A mutant. Therefore, N121 is a key amino acid residue in PVY VPg involved in B1 binding. These results highlight the potential of PVY VPg as a potential target for the development of antiviral agents.

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“…14,18 Therefore, dual PDE1B and PDE10A inhibitors that speci cally modulate striatal signalling cascades serve as a novel approach for treating schizophrenia's positive, cognitive, and negative symptoms as a whole via stimulation of D1 and suppression of D2 dopaminergic signalling. 19,20 Ligand-based pharmacophore modelling of in-silico computer-aided drug design is employed to augment the drug discovery process by excerpting shared chemical characteristics from the 3D structures of a known ligand set. 21 Lead identi cation is then carried out via virtual screening of natural product databases.…”

Section: Introductionmentioning

confidence: 99%

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

Soon

Gaurav

Gautam

2023

Preprint

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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.

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Identification of dual inhibitor of phosphodiesterase 1B/10A using structure-based drug design approach

Cited by 8 publications

References 65 publications

Evaluation of the acute oral toxicity and antipsychotic activity of a dual inhibitor of PDE1B and PDE10A in rat model of schizophrenia

Evaluation of the acute oral toxicity and antipsychotic activity of a dual inhibitor of PDE1B and PDE10A in rat model of schizophrenia

Tryptanthrin Derivative B1 Binds Viral Genome-Linked Protein (VPg) of Potato Virus Y

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

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