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The dopamine D2 Receptor (D2R) is a member of the G-Protein Coupled Receptor (GPCR) family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson’s disease. D2R is the target protein of the commonly used anti-psy...
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... Figure 4, the calculated interaction energies between the drugs and Asp114 using representative structures obtained from the docking and MD simulations were compared to the experimental binding energies. The chemical structures of ligands and hydrogen bonds they form with the Asp114 residue are shown in Figure 5. It should be noted that Class-I ligands have bulky struc- tures, whereas Class-II ligands have more linear or extended structures. ...
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Citations
... While DFT studies on antipsychotic drugs [129][130][131][132] and of antidepressants [133][134][135] are commonly found in the literature, works on the antioxidant activity of such compounds are still scarce. In a recent study by some of us, [123] the free radical scavenging activity of fluoxetine (20) and serotonin (18, Scheme 4) was investigated using a meta-hybrid functional (M06-2X [136]) in the gas phase and in the solvent. ...
Due to high oxygen consumption, the brain is particularly vulnerable to oxidative stress, which is considered an important element in the etiopathogenesis of several mental disorders, including schizophrenia, depression and dependencies. Despite the fact that it is not established yet whether oxidative stress is a cause or a consequence of clinic manifestations, the intake of antioxidant supplements in combination with the psychotropic therapy constitutes a valuable solution in patients’ treatment. Anyway, some drugs possess antioxidant capacity themselves and this aspect is discussed in this review, focusing on antipsychotics and antidepressants. In the context of a collection of clinical observations, in vitro and in vivo results are critically reported, often highlighting controversial aspects. Finally, a new challenge is discussed, i.e., the possibility of assessing in silico the antioxidant potential of these drugs, exploiting computational chemistry methodologies and machine learning. Despite the physiological environment being incredibly complex and the detection of meaningful oxidative stress biomarkers being all but an easy task, a rigorous and systematic analysis of the structural and reactivity properties of antioxidant drugs seems to be a promising route to better interpret therapeutic outcomes and provide elements for the rational design of novel drugs.
... However, there have been previous studies on the molecular docking of dopamine receptors such as D2 and D3 with drugs by DFT ( Thomas et al., 2016;Aranda et al., 2008). Salmas et al. have investigated the molecular docking of drugs such as risperidone, clozapine, aripiprazole, olanzapine, ziprasidone, and quetiapine with active sites of the D2 receptor in comparison with quantum mechanical approaches ( Salmas et al., 2018). ...
In order to find some clues as to why clozapine is a more effective drug than the sertindole and quetiapine, we investigated the molecular structures of these three molecules and calculated their structural properties by Density Functional Theory (DFT) technique. In this article, we suggested that clozapine has different binding
possibilities depending on the dopamine level in the medium. If so, it can be understood why clozapine is more effective in resolving clinical problems caused by different dopamine levels in the frontal and subcortical regions. To test this hypothesis, we measured the binding of three drugs to D1 and D2 dopamine receptors by molecular
docking. We found that clozapine had a greater potential for binding with D1 and D2 receptors. We suggested that this feature might give clozapine a higher therapeutic effect.
... Drugs related to schizophrenia and Parkinson's disease bind to different dopamine receptors that belong to the family of G-Protein-Coupled Receptors (GPCR). Previous investigations have modeled dopamine receptors, providing important information about the mechanism of ligand-receptor non-covalent interactions [46][47][48][49][50][51][52][53][54][55][56]. Nevertheless, little is known about the intrinsic reactivity of these drugs. ...
Schizophrenia and Parkinson's disease can be controlled with dopamine antagonists and agonists. In order to improve the understanding of the reaction mechanism of these drugs, in this investigation we present a quantum chemical study of 20 antagonists and 10 agonists. Electron donor acceptor capacity and global hardness are analyzed using Density Functional Theory calculations. Following this theoretical approach, we provide new insights into the intrinsic response of these chemical species. In summary, antagonists generally prove to be better electron acceptors and worse electron donors than dopamine, whereas agonists present an electron donor-acceptor capacity similar to that of dopamine. The chemical hardness is a descriptor that captures the resistance of a chemical compound to change its number of electrons. Within this model, harder molecules are less polarizable and more stable systems. Our results show that the global hardness is similar for dopamine and agonists whilst antagonists present smaller values. Following the Hard and Soft Acid and Bases principle, it is possible to conclude that dopamine and agonists are hard bases while antagonists are soft acids, and this can be related to their activity. From the electronic point of view, we have evolved a new perspective for the classification of agonist and antagonist, which may help to analyze future results of chemical interactions triggered by these drugs.
... Different authors hypothesized that DRs have a secondary binding pocket (SBP) next to the OBP, which was confirmed by the resolved crystal structures together with computational analyses [37,38,59]. Crystal structures of D2R (PDBid: 6CM4) [36] and D3R (PDBid: 3PBL) [37] and computational data suggest that 7.43Tyr is also a crucial amino-acid for interaction in the SBP [17,36,37]. 2.57Val was shown to form a hydrophobic pocket for antagonists like clozapine and haloperidole [57]. ...
... Different authors hypothesized that DRs have a secondary binding pocket (SBP) next to the OBP, which was confirmed by the resolved crystal structures together with computational analyses [37,38,59]. Crystal structures of D 2 R (PDBid: 6CM4) [36] and D 3 R (PDBid: 3PBL) [37] and computational data suggest that 7.43Tyr is also a crucial amino-acid for interaction in the SBP [17,36,37]. 2.57Val was shown to form a hydrophobic pocket for antagonists like clozapine and haloperidole [57]. ...
... One of the major research efforts in the research of dopamine receptors is the design of DR-subtype selective ligands [82]. However, most predictive studies have been performed on D 2 R ligand specificity, as this receptor is the most crucial in neurotransmission [17,57,83]. Herein, we present a comprehensive in silico approach, which reveals important interactions between DRs key residues and ligands in a more detailed way when compared with available literature [55,57,59,60,84,85]. ...
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
... We stress out that for clozapine, risperidone and aripiprazole, no cat-π-interactions could be identified at the D1-like DR. In addition, for risperidone, more hydrocontacts were found at the D1R and D4R (70,80) compared to the other DRs (2x 54, 59). Furthermore π-πstacking was favoured at the D3R (8 contacts), while for D1R and D2R 2 contacts were found, and for D4R and D5R 4 π-π-stacking interactions were found. ...
... One of the major research efforts in the research of dopamine receptors is the design of DR-subtype selective ligands [76]. However, most predictive studies have been performed on D2R ligand specificity, as this receptor is the most crucial in neurotransmission [48,77,80]. Our study reveals important interactions between DRs key residues and ligands in a more detailed way when compared with available literature [46,48,50,52,60,71] Data is also in line with experimental information, which corroborates the conceptual framework of this analysis protocol [38]. ...
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.
Benzodiazepines block the activity of nerves in the brain and the central nervous system whenever it is exceeded. The benzodiazepine derivatives such as CZ and OZ have been taken to characterize the molecular structure by spectroscopic and computational (by B3LYP/HSEH1PBE with 6-311++G(d,p) basis set) methods to obtain chemical, electronic and biological properties. The structures CZ and OZ have been optimized and complete vibrational assignments have been obtained. The transparency and the electronic transitions have been analyzed by UV-Vis spectrum. The maximum wavelength and band gap value obtained by UV-Vis analysis have been compared with HOMO-LUMO values due to delocalization of electrons. Chemical bonding by ELF and LOL, inter and intra-fragments interactions have been explained by scatter graph. Furthermore, acceptor and donor orbitals and nucleophilic and electrophilic interactions were explained using NBO and Fukui analyses. Chemically reactive site has been shown by MEP due to electronegative regions. The interaction of ligand molecule with appropriate proteins has been obtained and hence neurotransmission activities in the brain have been explained.
X-ray diffraction crystallography is the primary technique to determine the three-dimensional structures of biomolecules. Although a robust method, X-ray crystallography is not able to access the dynamical behavior of macromolecules. To do so, we have to carry out molecular dynamics simulations taking as an initial system the three-dimensional structure obtained from experimental techniques or generated using homology modeling. In this chapter, we describe in detail a tutorial to carry out molecular dynamics simulations using the program NAMD2. We chose as a molecular system to simulate the structure of human cyclin-dependent kinase 2.
Van der Waals forces are determinants of the formation of protein-ligand complexes. Physical models based on the Lennard-Jones potential can estimate van der Waals interactions with considerable accuracy and with a computational complexity that allows its application to molecular docking simulations and virtual screening of large databases of small organic molecules. Several empirical scoring functions used to evaluate protein-ligand interactions approximate van der Waals interactions with the Lennard-Jones potential. In this chapter, we present the main concepts necessary to understand van der Waals interactions relevant to molecular recognition of a ligand by the binding pocket of a protein target. We describe the Lennard-Jones potential and its application to calculate potential energy for an ensemble of structures to highlight the main features related to the importance of this interaction for binding affinity.
