scholarly journals A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1196 ◽  
Author(s):  
Beatriz Bueschbell ◽  
Carlos Barreto ◽  
António Preto ◽  
Anke Schiedel ◽  
Irina Moreira
Keyword(s):  
Dopamine Receptor ◽  
Electrostatic Interactions ◽  
Specific Binding ◽  
Binding Pocket ◽  
Binding Mode ◽  
Receptor Subtypes ◽  
Receptor Ligand ◽  
Selective Ligands ◽  
Ligand Interactions ◽  
New Treatments

Background: Selectively targeting dopamine receptors (DRs) has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases involving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like). Fifteen structurally diverse ligands were docked. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for selective binding to DR subtypes. Results: Residues of the aromatic microdomain were shown to be responsible for the majority of ligand interactions established to all DRs. Hydrophobic contacts involved a huge network of conserved and non-conserved residues between three transmembrane domains (TMs), TM2-TM3-TM7. Hydrogen bonds were mostly mediated by the serine microdomain. TM1 and TM2 residues were main contributors for the coupling of large ligands. Some amino acid groups form electrostatic interactions of particular importance for D1R-like selective ligands binding. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, which will support mutagenesis studies to improve the design of subtype-specific ligands.

scholarly journals A Complete Assessment of Dopamine Receptor-Ligand Interactions through Computational Methods

2019 ◽  
Author(s):  
Beatriz Bueschbell ◽  
Carlos A.V. Barreto ◽  
Antonio J. Preto ◽  
Anke C. Schiedel ◽  
Irina S. Moreira
Keyword(s):  
Dopamine Receptor ◽  
Electrostatic Interactions ◽  
Specific Binding ◽  
Binding Pocket ◽  
Binding Mode ◽  
Receptor Subtypes ◽  
Receptor Ligand ◽  
Pi Stacking ◽  
Ligand Interactions ◽  
New Treatments

Background: Selectively targeting dopamine receptors has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases evolving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like receptors). Fifteen structurally diverse ligands were docked to these models. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for DR sub-type specificity. Results: We showed that the number of conformations for a receptor:ligand complex was associated to unspecific interactions > 2.5 Å and hydrophobic contacts, while the decoys binding energy was influenced by specific electrostatic interactions. Known residues such as 3.32Asp, the serine microdomain and the aromatic microdomain were found interacting in a variety of modes (HB, SB, π-stacking). Purposed TM2-TM3-TM7 microdomain was found to form a hydrophobic network involving Orthosteric Binding Pocket (OBP) and Secondary Binding Pocket (SBP). T-stacking interactions revealed as especially relevant for some large ligands such as apomorphine, risperidone or aripiprazole. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, key for the design of more specific ligands.

scholarly journals Ab-initio binding of barnase–barstar with DelPhiForce steered Molecular Dynamics (DFMD) approach

2020 ◽  
Vol 19 (04) ◽  
pp. 2050016
Author(s):  
Mahesh Koirala ◽  
Emil Alexov
Keyword(s):  
Molecular Dynamics ◽  
Electrostatic Interactions ◽  
3D Structure ◽  
Binding Mode ◽  
Steered Molecular Dynamics ◽  
Biological Processes ◽  
Close Proximity ◽  
Ligand Interactions ◽  
Pulling Force

Receptor–ligand interactions are involved in various biological processes, therefore understanding the binding mechanism and ability to predict the binding mode are essential for many biological investigations. While many computational methods exist to predict the 3D structure of the corresponding complex provided the knowledge of the monomers, here we use the newly developed DelPhiForce steered Molecular Dynamics (DFMD) approach to model the binding of barstar to barnase to demonstrate that first-principles methods are also capable of modeling the binding. Essential component of DFMD approach is enhancing the role of long-range electrostatic interactions to provide guiding force of the monomers toward their correct binding orientation and position. Thus, it is demonstrated that the DFMD can successfully dock barstar to barnase even if the initial positions and orientations of both are completely different from the correct ones. Thus, the electrostatics provides orientational guidance along with pulling force to deliver the ligand in close proximity to the receptor.

scholarly journals Synthesis of novel 2-(piperazino-1-yl-alkyl)-1H-benzimidazole derivates and assessment of their interactions with the D2 dopamine receptor

2019 ◽  
Vol 84 (9) ◽  
pp. 925-934
Author(s):  
Jelena Penjisevic ◽  
Deana Andric ◽  
Vladimir Sukalovic ◽  
Goran Roglic ◽  
Vukic Soskic ◽  
...  
Keyword(s):  
Binding Site ◽  
Dopamine Receptor ◽  
Binding Pocket ◽  
D2 Dopamine Receptor ◽  
Competition Assay ◽  
Receptor Binding Site ◽  
Docking Analysis ◽  
Ligand Interactions ◽  
Methylene Groups ◽  
Dynamics Simulations

A total of 14 novel arylpiperazines were synthesized, and pharmacologically evaluated by measuring their affinities towards the D2 dopamine receptor (DRD2) in a [3H]spiperone competition assay. All the herein described compounds consist of a benzimidazole moiety connected to N-(2-methoxyphenyl)piperazine via linkers of various lengths. Molecular docking analysis and molecular dynamics simulations were performed on the DRD2?arylpiperazine complexes with the objective of exploring the receptor?ligand interactions and properties of the receptor binding site. The recently published crystal structure of DRD2 was used throughout this study. The major finding is that high affinity arylpiperazines must interact with both the orthosteric binding site and the extended binding pocket of DRD2 and therefore should contain a linker of 5 or 6 methylene groups long.

scholarly journals Heterogeneous and rate-dependent streptavidin–biotin unbinding revealed by high-speed force spectroscopy and atomistic simulations

2019 ◽  
Vol 116 (14) ◽  
pp. 6594-6601 ◽  
Author(s):  
Felix Rico ◽  
Andreas Russek ◽  
Laura González ◽  
Helmut Grubmüller ◽  
Simon Scheuring
Keyword(s):  
High Speed ◽  
Dynamic Range ◽  
Force Spectroscopy ◽  
Binding Pocket ◽  
Ensemble Averaging ◽  
Receptor Ligand ◽  
Binding Strength ◽  
Atomic Structures ◽  
Rate Dependent ◽  
Ligand Interactions

Receptor–ligand interactions are essential for biological function and their binding strength is commonly explained in terms of static lock-and-key models based on molecular complementarity. However, detailed information on the full unbinding pathway is often lacking due, in part, to the static nature of atomic structures and ensemble averaging inherent to bulk biophysics approaches. Here we combine molecular dynamics and high-speed force spectroscopy on the streptavidin–biotin complex to determine the binding strength and unbinding pathways over the widest dynamic range. Experiment and simulation show excellent agreement at overlapping velocities and provided evidence of the unbinding mechanisms. During unbinding, biotin crosses multiple energy barriers and visits various intermediate states far from the binding pocket, while streptavidin undergoes transient induced fits, all varying with loading rate. This multistate process slows down the transition to the unbound state and favors rebinding, thus explaining the long lifetime of the complex. We provide an atomistic, dynamic picture of the unbinding process, replacing a simple two-state picture with one that involves many routes to the lock and rate-dependent induced-fit motions for intermediates, which might be relevant for other receptor–ligand bonds.

scholarly journals Unravelling the binding mode of a methamphetamine aptamer: a spectroscopic and calorimetric investigation

2021 ◽  
Author(s):  
Clement Sester ◽  
Jordan AJ McCone ◽  
Ian Vorster ◽  
Joanne E Harvey ◽  
Justin M Hodgkiss
Keyword(s):  
Complex Formation ◽  
Small Molecule ◽  
Electrostatic Interactions ◽  
Structural Changes ◽  
High Specificity ◽  
Binding Mode ◽  
Titration Calorimetry ◽  
Strong Response ◽  
Binding Model ◽  
Ligand Interactions

Nucleic acid aptamers are bio-molecular recognition agents that bind to their targets with high specificity and affinity, and hold promise in a range of biosensor and therapeutic applications. In the case of small molecule targets, their small size and limited number of functional groups constitute challenges for their detection by aptamer-based biosensors because bio-recognition events may both be weak and produce poorly transduced signals. The binding affinity is principally used to characterize aptamer-ligand interactions; however a structural understanding of bio-recognition is arguably more valuable in order to design a strong response in biosensor applications. Using a combination of nuclear magnetic resonance, circular dichroism, and isothermal titration calorimetry, we propose a binding model for a new methamphetamine aptamer and determine the main interactions driving complex formation. These measurements reveal only modest structural changes to the aptamer upon binding and are consistent with a conformational selection binding model. The aptamer-methamphetamine complex formation was observed to be entropically driven, apparently involving hydrophobic and electrostatic interactions. Taken together, our results establish a means of elucidating small molecule-aptamer binding interactions, which may be decisive in the development of aptasensors and therapeutics, and may contribute to a deeper understanding of interactions driving aptamer selection.

scholarly journals Molecular Docking Study on the Binding Mode of Cardioselective Phenoxyaminopropanol Blocker into β-adrenergic Receptor Subtypes

2012 ◽  
Vol 59 (2) ◽  
pp. 44-53
Author(s):  
M. Polakovičová ◽  
R. Čižmáriková
Keyword(s):  
Molecular Docking ◽  
Adrenergic Receptor ◽  
Docking Study ◽  
Binding Pocket ◽  
Binding Mode ◽  
Receptor Subtypes ◽  
Molecular Docking Study ◽  
Subtype Selectivity ◽  
Extracellular Region ◽  
Selective Ligand

AbstractStructural understanding of subtype specific ligand-binding pocket variations and interactions of ligand with receptor may facilitate design of novel selective drugs. To gain insights into the subtype selectivity of β-blockers we performed flexible molecular docking study to analyze the interaction mode of cardioselective phenoxyaminopropanol blocker into the β1 and β2-adrenergic receptor. The binding site analysis reveals a strong identity between important amino acid residues and interactions with ligand in orthosteric catecholamine- binding pocket. The differences in the binding mode of selective ligand have been identified in the extracellular region of receptor subtypes.

scholarly journals Structural requirements for ligands of the δ-opioid receptor

2009 ◽  
Vol 74 (11) ◽  
pp. 1207-1217 ◽  
Author(s):  
Vuk Micovic ◽  
Milovan Ivanovic ◽  
Ljiljana Dosen-Micovic
Keyword(s):  
Opioid Receptor ◽  
Binding Pocket ◽  
Hydroxyl Group ◽  
Opioid Ligands ◽  
Chiral Compounds ◽  
Alkyl Groups ◽  
Selective Ligands ◽  
Ligand Interactions ◽  
Automated Docking ◽  
Δ Opioid Receptor

The ?-opioid receptor is sensitive to ligand geometry. In order to assist the synthesis of new ?-selective opioid ligands, the structure elements of ?-selective opioid ligands necessary for their effective binding were investigated. The automated docking procedure with a flexible ligand was used to simulate the binding of 17 ?-selective ligands to the ?-receptor. It was found that voluminous N-alkyl groups reduce the binding potency of naltrindole derivatives by preventing the ligands from adopting the preferred conformation in the receptor. This was confirmed by enantiospecific binding of chiral compounds where only one enantiomer adopts the naltrindole-like preferred conformation in the binding pocket. Voluminous groups replacing the hydroxyl group in the 3-hydroxybenzyl fragment of naltrindole analogs reduce the binding potency due to unfavorable steric interactions with the receptor. The two diastereoisomers of the potent ?-opioid ligand SNC80 confirmed the preferred binding conformation and the major receptor-ligand interactions.

Modulation of Platelet Activation by Native DNA – Initial Description of Platelet Receptor Type, Number and Discrimination for Native DNA

1981 ◽  
Vol 45 (03) ◽  
pp. 263-266 ◽  
Author(s):  
B A Fiedel ◽  
M E Frenzke
Keyword(s):  
Platelet Aggregation ◽  
Human Platelets ◽  
Scatchard Analysis ◽  
Type Number ◽  
Single Class ◽  
Receptor Ligand ◽  
Platelet Receptor ◽  
Platelet Binding ◽  
Ligand Interactions ◽  
Initial Description

SummaryNative DNA (dsDNA) induces the aggregation of isolated human platelets. Using isotopically labeled dsDNA (125I-dsDNA) and Scatchard analysis, a single class of platelet receptor was detected with a KD = 190 pM and numbering ~275/platelet. This receptor was discriminatory in that heat denatured dsDNA, poly A, poly C, poly C · I and poly C · poly I failed to substantially inhibit either the platelet binding of, or platelet aggregation induced by, dsDNA; by themselves, these polynucleotides were ineffective as platelet agonists. However, poly G, poly I and poly G · I effectively and competitively inhibited platelet binding of the radioligand, independently activated the platelet and when used at a sub-activating concentration decreased the extent of dsDNA stimulated platelet aggregation. These data depict a receptor on human platelets for dsDNA and perhaps certain additional polynucleotides and relate receptor-ligand interactions to a physiologic platelet function.

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