Figure 4 - uploaded by Ramin Ekhteiari Salmas
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The signal transduction pathway of the active model of D2R based on the NMA (Colour online). Note: The residues and the domains participated in the negative correlations are displayed as blue balls.
Source publication
G-protein-coupled receptors (GPCRs) are targets of more than 30% of marketed drugs. Investigation on the GPCRs may shed light on upcoming drug design studies. In the present study, we performed a combination of receptor- and ligand-based analysis targeting the dopamine D2 receptor (D2R). The signaling pathway of D2R activation and the construction...
Contexts in source publication
Context 1
... correlations are mainly associated with the conformational transition, which was occurring at the cytoplasmic half of the active state. In addition, in order to monitor the critical residues at the D2R active state which participated in the correlations, these pair residues are represented as blue balls in Figure 4. The correlation between the main residues at the active form is illus- trated with dashed lines (Figure 4). ...
Context 2
... addition, in order to monitor the critical residues at the D2R active state which participated in the correlations, these pair residues are represented as blue balls in Figure 4. The correlation between the main residues at the active form is illus- trated with dashed lines (Figure 4). Judging from the profile we found that all the correlations were established at the cytoplasmic half of the TM5, TM6, and TM7 domains. ...
Citations
... This method allows identification of sites with the greatest potential of affecting dynamics of a protein, at a modest computational cost, even in the absence of any information about the structure of possible modulators [70]. NMA was recently used to investigate vibrations in inactive and active D 2 receptor models, revealing an important role of TM5 in signal transduction [77]. ...
Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays a hot topic in medicinal chemistry. Allosteric modulators, i.e., compounds which bind in a receptor site topologically distinct from orthosteric sites, exhibit a number of advantages. They are more selective, safer and display a ceiling effect which prevents overdosing. Allosteric modulators of dopamine D2 receptor are potential drugs against a number of psychiatric and neurological diseases, such as schizophrenia and Parkinson’s disease. In this review, an insightful summary of current research on D2 receptor modulators is presented, ranging from their pharmacology and structural aspects of ligand-receptor interactions to their synthesis.
... The majority of orthosteric dopamine D2 receptor (D2R) ligands contain a protonatable nitrogen that is a key element of the classical pharmacophore model and the model constructed by Ekhteiari Salmas et al. [102]. The protonatable nitrogen is able to interact with the conserved residue Asp 3.32 , a proposed key anchor for basic moieties of aminergic ligands [103][104][105]. ...
G protein-coupled receptors (GPCRs) are amongst the most pharmaceutically relevant and well-studied protein targets, yet unanswered questions in the field leave significant gaps in our understanding of their nuanced structure and function. Three-dimensional pharmacophore models are powerful computational tools in in silico drug discovery, presenting myriad opportunities for the integration of GPCR structural biology and cheminformatics. This review highlights success stories in the application of 3D pharmacophore modeling to de novo drug design, the discovery of biased and allosteric ligands, scaffold hopping, QSAR analysis, hit-to-lead optimization, GPCR de-orphanization, mechanistic understanding of GPCR pharmacology and the elucidation of ligand–receptor interactions. Furthermore, advances in the incorporation of dynamics and machine learning are highlighted. The review will analyze challenges in the field of GPCR drug discovery, detailing how 3D pharmacophore modeling can be used to address them. Finally, we will present opportunities afforded by 3D pharmacophore modeling in the advancement of our understanding and targeting of GPCRs.
... The majority of orthosteric dopamine D2 receptor (D2R) ligands contain a protonatable nitrogen that is a key element of the classical pharmacophore model and the model constructed by Ekhteiari Salmas et al. [107]. The protonatable nitrogen is able to interact with the conserved residue Asp 3.32 , a proposed key anchor for basic moieties of aminergic ligands [108][109][110]. ...
G protein-coupled receptors (GPCRs) are amongst the most pharmaceutically relevant and well-studied protein targets, yet unanswered questions in the field leave significant gaps in our understanding of their nuanced structure and function. 3D pharmacophore models are powerful computational tools in silico drug discovery, presenting myriad opportunities for the integration of GPCR structural biology and cheminformatics. This review highlights success stories in the application of 3D pharmacophore modeling to de novo drug design, discovery of biased and allosteric ligands, scaffold hopping, QSAR analysis, hit-to-lead optimization, GPCR de-orphanization, mechanistic understanding of GPCR pharmacology and elucidation of ligand-receptor interactions. Furthermore, advances in the incorporation of dynamics and machine learning will be highlighted. The review will analyze challenges in the field of GPCR drug discovery, detailing how 3D pharmacophore modeling can be used to address them. Finally, we will present opportunities afforded by 3D pharmacophore modeling in the advancement of our understanding and targeting of GPCRs.
... In comparison with early reports, 3D-QSAR and 4D-QSAR approaches were regarded as useful strategies to construct pharmacophore features, and the most frequently used methods include Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Indices Analysis (CoMSIA) and GRID/ GOLPE program. The regression of the 3D-QSAR approach was applied using a partial least squares (PLS) algorithm to establish the optimal number of descriptors in structure-based pharmacophore modeling under PHASE software [40,41]. To build the 4D-QSAR model, the electron-conformational genetic algorithm (EC-GA) method was used to identify pharmacophore groups and bioactivity prediction based on electronic structure and conformational parameters [42,43]. ...
Drug-induced nephrotoxicity remains a common problem after exposure to medications and diagnostic agents, which may be heightened in the kidney microenvironment and deteriorate kidney function. In this study, the toxic effects of fourteen marked drugs with the individual chemical structure were evaluated in kidney cells. The quantitative structure-activity relationship (QSAR) approach was employed to investigate the potential structural descriptors of each drug-related to their toxic effects. The most reasonable equation of the QSAR model displayed that the estimated regression coefficients such as the number of ring assemblies, three-membered rings, and six-membered rings were strongly related to toxic effects on renal cells. Meanwhile, the chemical properties of the tested compounds including carbon atoms, bridge bonds, H-bond donors, negative atoms, and rotatable bonds were favored properties and promote the toxic effects on renal cells. Particularly, more numbers of rotatable bonds were positively correlated with strong toxic effects that displayed on the most toxic compound. The useful information discovered from our regression QSAR models may help to identify potential hazardous moiety to avoid nephrotoxicity in renal preventive medicine.
... The aim of our work was to construct full models of the dopamine D2 receptor D2S and D2L isoforms in complex with a natural agonist, dopamine, and to study the coupling of these isoforms with Gi1 and Gi2 proteins, as the experimental data about D2S and D2L isoforms and Gi protein subtype preference remains unclear [6,8]. Although models of the dopamine D2 receptor in active conformation with or without the respective G protein are already available in the literature [28][29][30][31], this is, to our best knowledge, the first time full D2S and D2L isoforms, including ICL3 loop, have been modeled. Modeling of ICL3 in the case of GPCRs with a long ICL3 is a challenge as there are no templates for this highly flexible protein fragment. ...
The dopamine D2 receptor belongs to rhodopsin-like G protein-coupled receptors (GPCRs) and it is an important molecular target for the treatment of many disorders, including schizophrenia and Parkinson's disease. Here, computational methods were used to construct the full models of the dopamine D2 receptor short (D2S) and long (D2L) isoforms (differing with 29 amino acids insertion in the third intracellular loop, ICL3) and to study their coupling with Gi1 and Gi2 proteins. It was found that the D2L isoform preferentially couples with the Gi2 protein and D2S isoform with the Gi1 protein, which is in accordance with experimental data. Our findings give mechanistic insight into the interplay between isoforms of dopamine D2 receptors and Gi proteins subtypes, which is important to understand signaling by these receptors and their mediation by pharmaceuticals, in particular psychotic and antipsychotic agents.
... In a study by Salmas et al. (2016) top-scored pharmacophore models were made using 38 dopamine D2 receptor ligands (training set) using PHASE modeling. 15 test set compounds were used to validate the models. ...
Schizophrenia is a chronic neurological disorder in which a person suffers from emotional and intellectual disturbances. First generation antipsychotics for Schizophrenia were replaced with by second generation ones with less side-effects like Parkinsonism and Hyperprolactinemia. A novel, computer-based drug designing technique, has emerged to develop more efficient drugs. One of the computational methods becoming increasingly popular to develop new drugs is relying on Pharmacophores. This method was utilized to develop pharmacophore models of Akt2 inhibitors and β2-Adrenoceptor agonists. A pharmacophore model is proposed, using fourteen second generation and one first generation antipsychotic drugs for Schizophrenia that are effective against both 5-HT2a and D2 receptors. Hydrogen bond acceptors (HBA), aromatic rings (AR ring) and positive ionizable (PI) groups were identified computationally as pharmacophore features by LigandScout. The distance range calculated by Visual Molecular Dynamics (VMD) between AR-HBA, AR-PI and HBA- PI was 3.68 A°-5.74 A°, 5.66 A°-7.64 A° and 3.77 A°-5.38 A°, respectively. This study should help finding specific and more efficient drugs for Schizophrenia in future.
... Other methods can be used to identify important structures in the activation of dopamine receptors. A study bySalmas, Stein, et al. (2017) ...
The dopamine D2 receptor (D2R) is the primary target for antipsychotic drugs. Besides schizophrenia, this receptor is linked to dementia, Parkinson’s disease, and depression. Recent studies have shown that β-arrestin biased agonists at this receptor treat schizophrenia with less side effects. Although the high resolution structure of this receptor exists, the mechanism of biased agonism at the receptor is unknown. In this study, dopamine, the endogenous unbiased G-protein agonist, MLS1547, a G-protein biased agonist, and UNC9975, a G-protein antagonist and a β-arrestin biased agonist, were docked to a homology model of the whole D2R including all flexible loops, and molecular dynamics simulations were conducted to study the potential mechanisms of biased agonism. Our thorough analysis on the protein–ligand interaction, secondary structure, tertiary structure, structure dynamics, and molecular switches of all three systems indicates that ligand binding to transmembrane 3 might be essential for G-protein recruitment, while ligand binding to transmembrane 6 might be essential for β-arrestin recruitment. Our analysis also suggests changes in both the secondary and the tertiary structures of TM5 and TM7, molecular switches and ICL3 flexibility are important in biased signaling.
Communicated by Ramaswamy H. Sarma
... The key element of this model is a protonatable nitrogen atom which is able to interact with the conserved Asp(3.32). A positively charged group is also a key element of the pharmacophore model recently constructed for the dopamine D 2 receptor antagonists (Ekhteiari Salmas et al. 2016). It was found that common pharmacophore motives for the dopamine D 2 receptor antagonists include AADPR, AADRR, AAHPR, AAPRR, ADHRR, ADPRR, AHHPR, AHHRR, AHPRR, and HHPRR ("A"-hydrogen bond acceptor, "D"-hydrogen bond donor, "H"-hydrophobic group, "P"-positively charged group, and "R"-aromatic ring), however the highest correlation coefficients for training set and test set compounds were found as 0.95 and 0.75, respectively at the AADPR.671 ...
The dopaminergic hypothesis of schizophrenia is the main concept explaining the direct reasons of schizophrenia and the effectiveness of current antipsychotics. All antipsychotics present on the market are potent dopamine D2 receptor antagonists or partial agonists. In this work we investigate a series of dopamine D2 receptor antagonists which do not fulfill the criteria of the classical pharmacophore model as they do not possess a protonatable nitrogen atom necessary to interact with the conserved Asp(3.32). Such compounds are interesting, inter alia, due to possible better pharmacokinetic profile when compared to basic, ionizable molecules. By means of homology modeling, molecular docking and molecular dynamics we determined that the compounds investigated interact with Asp(3.32) via their amide nitrogen atom. It was found that the studied compounds stabilize the receptor inactive conformation through the effect on the ionic lock, which is typical for GPCR antagonists. We constructed a CoMFA model for the studied compounds with the following statistics: R2 = 0.95, Q2 = 0.63. The quality of the CoMFA model was confirmed by high value of R2 of the test set, equal 0.96. The CoMFA model indicated two regions where bulky substituents are favored and two regions where bulky substituents are not beneficial. Two red contour regions near carbonyl groups were identified meaning that negative charge would be favored here. Furthermore, the S-oxide group is connected with blue contour region meaning that positive charge is favored in this position. These findings may be applied for further optimization of the studied compound series.
... The dopamine molecule also binds to dopamine receptors (class of G-protein-coupled receptors) which are involved in cell signaling processes and their dysfunction is associated with Schizophrenia ad Parkinson's diseases. Several modeling, MD simulation, and 3D-QSAR studies are performed for dopamine (D 2 R and D 3 R) and Mu/ Kappa-Opioid receptors to identify or design novel inhibitor molecules for these receptors (Bera, Marathe, Payghan, & Ghoshal, 2017;Salmas, Stein, Yurtsever, & Seeman, 2016;Salmas, Yurtsever, & Durdagi, 2016;Xie, Wang, Li, & Xu, 2016). In hMAO B, the substrate (dopamine) binding cavity is oval shaped and lined by Leu171, Cys172, Tyr398, Ile198, Ile199, Tyr435, Tyr60, Tyr326, Phe343, and Tyr188 residues (Binda, Newton-Vinson, Hubálek, Edmondson, & Mattevi, 2002;Binda et al., 2004). ...
The human Monoamine oxidase (hMAO) metabolizes several biogenic amine neurotransmitters and involves in different neurological disorders. Extensive MD- simulation studies of dopamine docked hMAO B structures have revealed the stabilization of amino-terminal of the substrate by a direct and water-mediated interaction of catalytic tyrosines, Gln206, and Leu171 residues. The catechol ring of the substrate is stabilized by Leu171(C-H) ···π(Dop)···(H-C) Ile199 interaction. Several conserved water molecules are observed to play role in the recognition of substrate to the enzyme, where W1 and W2 associate in dopamine- FAD interaction, reversible dynamics of W3 and W4 influenced the coupling of Tyr435 to Trp432 and FAD, W5 and W8 stabilized the catalytic Tyr188/398 residues. The W6, W7, and W8 water centers are involved in the recognition of catalytic residues and FAD with the N(+)- site of dopamine through hydrogen bonding interaction. The recognition of substrate to gating residues is made through W9, W10, and W11 water centers. Beside the interplay of water molecules, the catalytic aromatic cage has also been stabilized by π···water, π···C-H, and π··· π interactions. The topology of conserved water molecular sites along with the hydration dynamics of catalytic residues, FAD and dopamine have added a new feature on the substrate binding chemistry in hMAO B which may be useful for substrate analog inhibitor design.
Glucose-Methanol-Choline (GMC) family enzymes are very important in catalyzing the oxidation of a wide range of structurally diverse substrates. Enzymes that constitute the GMC family, share a common tertiary fold but < 25% sequence identity. Cofactor FAD, FAD binding signature motif, and similar structural scaffold of the active site are common features of oxidoreductase enzymes of the GMC family. Protein functionality mainly depends on protein three-dimensional structures and dynamics. In this study, we used the normal mode analysis method to search the intrinsic dynamics of GMC family enzymes. We have explored the dynamical behavior of enzymes with unique substrate catabolism and active site characteristics from different classes of the GMC family. Analysis of individual enzymes and comparative ensemble analysis of enzymes from different classes has shown conserved dynamic motion at FAD binding sites. The present study revealed that GMC enzymes share a strong dynamic similarity (Bhattacharyya coefficient >90% and root mean squared inner product >52%) despite low sequence identity across the GMC family enzymes. The study predicts that local deformation energy between atoms of the enzyme may be responsible for the catalysis of different substrates. This study may help that intrinsic dynamics can be used to make meaningful classifications of proteins or enzymes from different organisms.Communicated by Ramaswamy H. Sarma.
