Fragment‐ and negative image‐based screening of phosphodiesterase 10A inhibitors

Jokinen, Elmeri M.; Postila, Pekka A.; Ahinko, Mira; Niinivehmas, Sanna; Pentikäinen, Olli T.

doi:10.1111/cbdd.13584

Cited by 11 publications

(11 citation statements)

References 58 publications

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“…PANTHER re-scoring has been shown to provide significant enrichment of active compounds in VS with various protein targets [25] , [26] . In addition, a fragment-based approach for NIB-screening was utilized by incorporating 1P3 molecules extracted from the MixMD simulations into the NIB-models [20] . Multiple coordinate points for each model were used.…”

Section: Methodsmentioning

confidence: 99%

“…As a result, expensive, laborious and time-consuming experimental testing can be focused on the highlighted compounds. Computational tools such as molecular docking enable extremely fast virtual screening (VS) of molecular libraries to detect the most potential binders to a disease-related protein target [20] , [21] , [22] , [23] , [24] . Accuracy of docking can typically be improved by utilizing a different scoring function to re-score ligand poses generated by the docking software [25] , [26] , [27] , [28] .…”

Section: Introductionmentioning

confidence: 99%

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Detection of Binding Sites on SARS-CoV-2 Spike Protein Receptor-Binding Domain by Molecular Dynamics Simulations in Mixed Solvents

Jokinen

Gopinath

Kurkinen

et al. 2021

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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The novel SARS-CoV-2 uses ACE2 (Angiotensin-Converting Enzyme 2) receptor as an entry point. Insights on S protein receptor-binding domain (RBD) interaction with ACE2 receptor and drug repurposing has accelerated drug discovery for the novel SARS-CoV-2 infection. Finding small molecule binding sites in S protein and ACE2 interface is crucial in search of effective drugs to prevent viral entry. In this study, we employed molecular dynamics simulations in mixed solvents together with virtual screening to identify small molecules that could be potential inhibitors of S protein -ACE2 interaction. Observation of organic probe molecule localization during the simulations revealed multiple sites at the S protein surface related to small molecule, antibody, and ACE2 binding. In addition, a novel conformation of the S protein was discovered that could be stabilized by small molecules to inhibit attachment to ACE2. The most promising binding site on RBD-ACE2 interface was targeted with virtual screening and top-ranked compounds (DB08248, DB02651, DB03714, and DB14826) are suggested for experimental testing. The protocol described here offers an extremely fast method for characterizing key proteins of a novel pathogen and for the identification of compounds that could inhibit or accelerate spreading of the disease.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detection of Binding Sites on SARS-CoV-2 Spike Protein Receptor-Binding Domain by Molecular Dynamics Simulations in Mixed Solvents

Jokinen

Gopinath

Kurkinen

et al. 2021

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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“…Phosphodiesterase 10A inhibitors: PDE10A inhibitors are known to have antipsychotic property and are also thought to be neuroprotective [90]. PDE10A is abundant in striatum and is a key regulator of basal ganglia circuitry modulating cortical motor activity.…”

Section: Synaptic Modulationmentioning

confidence: 99%

Multimodal treatment strategies in Huntington’s disease

Dutta¹

2021

Neurosci Neurol Disord

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Huntington’s disease (HD) is an incurable neurodegenerative disease that causes involuntary movements, emotional lability, and cognitive dysfunction. HD symptoms usually develop between ages 30 and 50, but can appear as early as 2 or as late as 80 years. Currently no neuroprotective and neurorestorative interventions are available. Early multimodal intervention in HD is only possible if the genetic diagnosis is made early. Early intervention in HD is only possible if genetic diagnosis is made at the disease onset or when mild symptoms manifest. Growing evidence and understanding of HD pathomechanism has led researchers to new therapeutic targets. Here, in this article we will talk about the multimodal treatment strategies and recent advances made in this field which can be used to target the HD pathogenesis at its most proximal level.

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“…1a) [40,42]. This is analogous to matching the charge/shape properties between the receptors' ligand-binding sites with those of the ligands during docking [133][134][135][136], docking rescoring [137][138][139], or drug discovery [136,[140][141][142]. In fact, there is overwhelming evidence of the affinity of small molecules towards lipids [28], and the MLC is also known to affect drug membrane permeability [143].…”

Section: The Effect Of Membrane Sorting For Drugs and Beyondmentioning

confidence: 99%

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

Postila

Róg

2019

Mol Neurobiol

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Synaptic neurotransmission is generally considered as a function of membrane-embedded receptors and ion channels in response to the neurotransmitter (NT) release and binding. This perspective aims to widen the protein-centric view by including another vital component-the synaptic membrane-in the discussion. A vast set of atomistic molecular dynamics simulations and biophysical experiments indicate that NTs are divided into membrane-binding and membrane-nonbinding categories. The binary choice takes place at the water-membrane interface and follows closely the positioning of the receptors' binding sites in relation to the membrane. Accordingly, when a lipophilic NT is on route to a membrane-buried binding site, it adheres on the membrane and, then, travels along its plane towards the receptor. In contrast, lipophobic NTs, which are destined to bind into receptors with extracellular binding sites, prefer the water phase. This membrane-based sorting splits the neurotransmission into membraneindependent and membrane-dependent mechanisms and should make the NT binding into the receptors more efficient than random diffusion would allow. The potential implications and notable exceptions to the mechanisms are discussed here. Importantly, maintaining specific membrane lipid compositions (MLCs) at the synapses, especially regarding anionic lipids, affect the level of NT-membrane association. These effects provide a plausible link between the MLC imbalances and neurological diseases such as depression or Parkinson's disease. Moreover, the membrane plays a vital role in other phases of the NT life cycle, including storage and release from the synaptic vesicles, transport from the synaptic cleft, as well as their synthesis and degradation.

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Fragment‐ and negative image‐based screening of phosphodiesterase 10A inhibitors

Cited by 11 publications

References 58 publications

Detection of Binding Sites on SARS-CoV-2 Spike Protein Receptor-Binding Domain by Molecular Dynamics Simulations in Mixed Solvents

Detection of Binding Sites on SARS-CoV-2 Spike Protein Receptor-Binding Domain by Molecular Dynamics Simulations in Mixed Solvents

Multimodal treatment strategies in Huntington’s disease

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

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