scholarly journals Investigation of the Selectivity of L-Type Voltage-Gated Calcium Channels 1.3 for Pyrimidine-2,4,6-Triones Derivatives Based on Molecular Dynamics Simulation

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5440
Author(s):  
Qi Ye ◽  
Zhenyu Zhang ◽  
Wenying Zhang ◽  
Yushan Ding ◽  
Fan Zhao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Amino Acid Residues ◽  
Voltage Gated Calcium Channels ◽  
Cardiovascular Side Effects ◽  
Highly Hydrophobic ◽  
Polar Substituents ◽  
Vdw Interaction

Human Cav1.3 (hCav1.3) is of great interest as a potential target for Parkinson’s disease. However, common medications like dihydropyridines (DHPs), a kind of classic calcium channel blocker, have poor selectivity to hCav1.3 in clinical treatment, mainly due to being implicated in cardiovascular side-effects mediated by human Cav1.2 (hCav1.2). Recently, pyrimidine-2,4,6-triones (PYTs) have received extensive attention as prominent selective inhibitors to hCav1.3. In this study, we describe the selectivity mechanism of PYTs for hCav1.2 and hCav1.3 based on molecular dynamic simulation methods. Our results reveal that the van der Waals (vdW) interaction was the most important force affecting selectivity. Moreover, the hydrophobic interaction was more conducive to the combination. The highly hydrophobic amino acid residues on hCav1.3, such as V162 (IR1), L303 (IR2), M481 (IR3), and F484 (IR3), provided the greatest contributions in the binding free energy. On the other hand, the substituents of a halogen-substituted aromatic ring, cycloalkyl and norbornyl on PYTs, which are pertinent to the steric hindrance of the compounds, played core roles in the selectivity and affinity for hCav1.3, whereas strong polar substituents needed to be avoided. The findings could provide valuable information for designing more effective and safe medicines for Parkinson’s disease.

MOLECULAR MODELING OF THE INTERACTIONS BETWEEN HISTONE DEACETYLASE 8 AND INHIBITORS

2012 ◽  
Vol 11 (04) ◽  
pp. 907-924 ◽  
Author(s):  
DAWEI HUANG ◽  
XIAOHUI LI ◽  
ZHILONG XIU
Keyword(s):  
Molecular Dynamics ◽  
Histone Deacetylases ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Zinc Ion ◽  
Dynamics Simulation ◽  
Amino Acid Residues ◽  
Domain Docking ◽  
Dynamics Simulations ◽  
Linker Domain

Inhibitors of histone deacetylases (HDACs) have become an attractive class of anticancer agent. To understand the interaction between HDAC8 and inhibitors, including "pan-" inhibitors that inhibit many HDACs isoforms and selective inhibitors with no linker domain, docking and molecular dynamics simulation were conducted. Docking results showed the presence of π-π interactions between "linkerless" inhibitors and the aromatic amino acid residues of HDAC8 in the active site. Binding between HDAC8 and inhibitors was also stabilized by hydrogen bond and hydrophobic interaction. In molecular dynamics simulations, the zinc ion was shown to coordinate one more atom of HDAC8-"linkerless" inhibitor complexes than HDAC8-"pan-" inhibitor complexes. Persistent hydrogen bonds also existed between Tyr306 of HDAC8 and some inhibitors. When inhibitors with large cap groups bound to the active pocket of HDAC8, Phe152 and Met274 shifted from their initial positions and the entrance of the active pocket became more open, resulting in the formation of sub-pocket. Hydrophobic interactions contributed most favorably to the binding free energy between HDAC8 and inhibitors. Lys33, Asp178, Asp267, Tyr306 and Leu308 of HDAC8 were favorable for binding with all inhibitors.

How Parkinson's disease-related mutations disrupt the dimerization of WD40 domain in LRRK2: a comparative molecular dynamics simulation study

2020 ◽  
Vol 22 (36) ◽  
pp. 20421-20433
Author(s):  
Xinyi Li ◽  
Mingyu Ye ◽  
Yue Wang ◽  
Ming Qiu ◽  
Tingting Fu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Molecular Dynamics ◽  
Parkinson's Disease ◽  
Molecular Dynamics Simulation ◽  
Neurodegenerative Disease ◽  
Simulation Study ◽  
Dynamics Simulation ◽  
Pathogenic Factor ◽  
Leucine Rich Repeat ◽  
Wd40 Domain

The multidomain kinase enzyme leucine-rich-repeat kinase 2 (LRRK2), activated through a homodimerization manner, is identified as an important pathogenic factor in Parkinson's disease (PD), the second most common neurodegenerative disease wordwide.

scholarly journals Adenosine A1 Receptor Ligands Bind to α-Synuclein: Implications for α-Synuclein Misfolding and α-Synucleinopathy in Parkinson’s Disease

2020 ◽  
Author(s):  
Elisabet Jakova ◽  
Mohamed Taha Moutaoufik ◽  
Jeremy Lee ◽  
Mohan Babu ◽  
Francisco Sandoval Cayabyab
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Adenosine A1 Receptor ◽  
Dynamics Simulation ◽  
Receptor Ligands ◽  
N Terminus ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Loop Conformation

Abstract Background:Accumulating α-synuclein (α-Syn) aggregates in neurons and glial cells are the staples of many synucleinopathy disorders, such as Parkinson’s disease. Since brain adenosine becomes greatly elevated in ageing brains and chronic adenosine A1 receptor (A1R) stimulation leads to neurodegeneration, we determined whether adenosine or A1R receptor ligands mimic the action of known compounds that promote α-Syn aggregation (e.g., the amphetamine analogue 2-aminoindan) or inhibit α-Syn aggregation (e.g., Rasagiline metabolite 1-aminoindan). In the present study, we determined whether adenosine, the A1R receptor agonist N6-Cyclopentyladenosine (CPA) and antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) directly interact with α-Syn to modulate α-Syn aggregation and neurodegeneration of dopaminergic neurons in the substantia nigra (SN). Methods:Nanopore analysis and molecular dynamics simulation were used to test the binding properties of CPA and DPCPX with α-Syn in vitro. Sprague-Dawley rats were administered 7-day intraperitoneal injections of the A1R ligands and 1- and 2-aminoindan, and levels of α-Syn aggregation and neurodegeneration were examined in the substantia nigra pars compacta region. Results:Using nanopore analysis, we showed that the A1R agonists (CPA and adenosine) interacted with the N-terminus of α-Syn, similar to 2-aminoindan, which is expected to promote a “knot” conformation and α-Syn misfolding. In contrast, the A1R antagonist DPCPX interacted with the N- and C-termini of α-Syn, similar to 1-aminoindan, which is expected to promote a “loop” conformation which prevents α-Syn misfolding. Molecular docking studies revealed that adenosine, CPA and 2-aminoindan interacted with the hydrophobic core of α-Syn N-terminus, whereas DPCPX and 1-aminoindan showed direct binding to the N- and C-terminal hydrophobic pockets. Histological and confocal imaging studies revealed that chronic treatments with CPA alone or in combination with 2-aminoindan increased α-Syn aggregation and neurodegeneration in SN pars compacta. In contrast, DPCPX and 1-aminoindan attenuated CPA-induced neurodegeneration but did not significantly reduce α-Syn aggregation.Conclusions:The results indicate A1R agonists and drugs promoting a “knot” conformation of α-Syn can cause α-synucleinopathy and increase neuronal degeneration, whereas A1R antagonists and drugs promoting a “loop” conformation of α-Syn can be harnessed for possible neuroprotective therapies to decrease α-synucleinopathy in Parkinson’s disease.

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