Abstract:An increasing number of G protein-coupled receptor (GPCR) crystal structures provide important—albeit static—pictures of how small molecules or peptides interact with their receptors. These high-resolution structures represent a tremendous opportunity to apply molecular dynamics (MD) simulations to capture atomic-level dynamical information that is not easy to obtain experimentally. Understanding ligand binding and unbinding processes, as well as the related responses of the receptor, is crucial to the design … Show more
“…These results indicated that TCDD has stronger binding affinity towards mVEGFR1 compared to hVEGFR1. Further, crystal structure of mVEGFR1 is not available and only a part of mVEGFR1 as recombinant mouse soluble VEGFR-1 D7 /Fc chimera is available 38,39 . Therefore, we conducted experimental studies followed by molecular dynamic simulations on hVEGFR1.Figure 3Docking poses of VEGFR1 interaction with the TCDD.…”
Section: Resultsmentioning
confidence: 99%
“…Understanding the binding of a ligand typically to a substrate or a regulator is a dynamic process and is key in understanding the function itself 32 . MDS has been used successfully in elucidating ligand-induced perturbations in several studies reported previously 35–39 . In the present study, to analyse the conformational changes between hVEGFR1 and hVEGFR1-TCDD complexes, we performed MDS.…”
The toxic manifestations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant, primarily depend on its ability to activate aryl hydrocarbon receptor (AhR), which is a ligand-dependent transcription factor belonging to the superfamily of basic-helix-loop-helix DNA-binding proteins. In the present study, we aimed to identify novel protein receptor targets for TCDD using computational and
in vitro
validation experiments. Interestingly, results from computational methods predicted that Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) could be one of the potential targets for TCDD in both mouse and humans. Results from molecular docking studies showed that human VEGFR1 (hVEGFR1) has less affinity towards TCDD compared to the mouse VEGFR1 (mVEGFR1).
In vitro
validation results showed that TCDD can bind and phosphorylate hVEGFR1. Further, results from molecular dynamic simulation studies showed that hVEGFR1 interaction with TCDD is stable throughout the simulation time. Overall, the present study has identified VEGFR1 as a novel target for TCDD, which provides the basis for further elucidating the role of TCDD in angiogenesis.
“…These results indicated that TCDD has stronger binding affinity towards mVEGFR1 compared to hVEGFR1. Further, crystal structure of mVEGFR1 is not available and only a part of mVEGFR1 as recombinant mouse soluble VEGFR-1 D7 /Fc chimera is available 38,39 . Therefore, we conducted experimental studies followed by molecular dynamic simulations on hVEGFR1.Figure 3Docking poses of VEGFR1 interaction with the TCDD.…”
Section: Resultsmentioning
confidence: 99%
“…Understanding the binding of a ligand typically to a substrate or a regulator is a dynamic process and is key in understanding the function itself 32 . MDS has been used successfully in elucidating ligand-induced perturbations in several studies reported previously 35–39 . In the present study, to analyse the conformational changes between hVEGFR1 and hVEGFR1-TCDD complexes, we performed MDS.…”
The toxic manifestations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant, primarily depend on its ability to activate aryl hydrocarbon receptor (AhR), which is a ligand-dependent transcription factor belonging to the superfamily of basic-helix-loop-helix DNA-binding proteins. In the present study, we aimed to identify novel protein receptor targets for TCDD using computational and
in vitro
validation experiments. Interestingly, results from computational methods predicted that Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) could be one of the potential targets for TCDD in both mouse and humans. Results from molecular docking studies showed that human VEGFR1 (hVEGFR1) has less affinity towards TCDD compared to the mouse VEGFR1 (mVEGFR1).
In vitro
validation results showed that TCDD can bind and phosphorylate hVEGFR1. Further, results from molecular dynamic simulation studies showed that hVEGFR1 interaction with TCDD is stable throughout the simulation time. Overall, the present study has identified VEGFR1 as a novel target for TCDD, which provides the basis for further elucidating the role of TCDD in angiogenesis.
“…Computational and simulation methods can play useful roles in drug discovery as well. These methods have helped improve our understanding of GPCRs' structures and functions [2,[46][47][48][49]. There are three main requirements for an MD simulation: the model system, the force field, and the MD simulation software.…”
Section: New Insights From Molecular Dynamics Simulationsmentioning
G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. There is evidence that some ligands that bind to the GPCRs activate different downstream signaling pathways. G protein activation or -arrestin biased signaling involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. Molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators' interactions between receptors and ligands. Here, we highlight recent simulation studies and methods used to study biased G protein-coupled receptor signaling and their conformational dynamics. We also highlight applications of MD simulations to drug discovery.
“…As of February 2019, there are 59 unique receptor structures solved (https://gpcrdb.org/structure/statistics), most of them corresponding to the rhodopsin (or class A) family (Figure 1). Molecular dynamics (MD) simulations started from these experimental structures have provided very important insights into ligand binding and receptor activation (Miao and McCammon, 2016; Sengupta et al, 2016; Latorraca et al, 2017; Marino and Filizola, 2018; Torrens-Fontanals et al, 2018; Velgy et al, 2018).…”
Human G-protein coupled receptors (GPCRs) convey a wide variety of extracellular signals inside the cell and they are one of the main targets for pharmaceutical intervention. Rational drug design requires structural information on these receptors; however, the number of experimental structures is scarce. This gap can be filled by computational models, based on homology modeling and docking techniques. Nonetheless, the low sequence identity across GPCRs and the chemical diversity of their ligands may limit the quality of these models and hence refinement using molecular dynamics simulations is recommended. This is the case for olfactory and bitter taste receptors, which constitute the first and third largest GPCR groups and show sequence identities with the available GPCR templates below 20%. We have developed a molecular dynamics approach, based on the combination of molecular mechanics and coarse grained (MM/CG), tailored to study ligand binding in GPCRs. This approach has been applied so far to bitter taste receptor complexes, showing significant predictive power. The protein/ligand interactions observed in the simulations were consistent with extensive mutagenesis and functional data. Moreover, the simulations predicted several binding residues not previously tested, which were subsequently verified by carrying out additional experiments. Comparison of the simulations of two bitter taste receptors with different ligand selectivity also provided some insights into the binding determinants of bitter taste receptors. Although the MM/CG approach has been applied so far to a limited number of GPCR/ligand complexes, the excellent agreement of the computational models with the mutagenesis and functional data supports the applicability of this method to other GPCRs for which experimental structures are missing. This is particularly important for the challenging case of GPCRs with low sequence identity with available templates, for which molecular docking shows limited predictive power.
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