Exploring the binding properties of agonists interacting with human TGR5 using structural modeling, molecular docking and dynamics simulations

Sindhu, Thangaraj; Srinivasan, Pappu

doi:10.1039/c4ra16617e

Cited by 37 publications

(18 citation statements)

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“…The Rg is an evaluating parameter for the behavior and stability of the biological systems during the MD trajectories by measuring the compactness of biomacromolecules’ structures [ 94 , 95 ]. The Rg can also be used as an indicator of whether the complex will maintain folded conformation after the MD simulation.…”

Section: Resultsmentioning

confidence: 99%

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Alamri

Qamar

Mirza

et al. 2020

Journal of Pharmaceutical Analysis

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The papain-like protease (PL pro ) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PL pro , that can be further developed as potential pan-PL pro based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PL pro were exploited, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease inhibitors database composed of ∼7000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PL pro and showed consistent interaction profile with SARS-CoV PL pro and MERS-CoV PL pro as well. Conclusively, the reported SARS-CoV-2 PL pro specific compounds could serve as seeds for developing potent pan-PL pro based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.

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Section: Resultsmentioning

confidence: 99%

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Alamri

Qamar

Mirza

et al. 2020

Journal of Pharmaceutical Analysis

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“…Homology models of TGR5 have been presented based on template structures of other seven transmembrane (7TM) domain receptors5678. We previously reported that the amino acids 285–294 at the TGR5 C-terminus form an alpha-helical stretch important for plasma membrane localization and thus responsiveness to extracellular ligands9.…”

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confidence: 99%

Structural assemblies of the di- and oligomeric G-protein coupled receptor TGR5 in live cells: an MFIS-FRET and integrative modelling study

Greife

Felekyan

et al. 2016

Sci Rep

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TGR5 is the first identified bile acid-sensing G-protein coupled receptor, which has emerged as a potential therapeutic target for metabolic disorders. So far, structural and multimerization properties are largely unknown for TGR5. We used a combined strategy applying cellular biology, Multiparameter Image Fluorescence Spectroscopy (MFIS) for quantitative FRET analysis, and integrative modelling to obtain structural information about dimerization and higher-order oligomerization assemblies of TGR5 wildtype (wt) and Y111 variants fused to fluorescent proteins. Residue 111 is located in transmembrane helix 3 within the highly conserved ERY motif. Co-immunoprecipitation and MFIS-FRET measurements with gradually increasing acceptor to donor concentrations showed that TGR5 wt forms higher-order oligomers, a process disrupted in TGR5 Y111A variants. From the concentration dependence of the MFIS-FRET data we conclude that higher-order oligomers – likely with a tetramer organization - are formed from dimers, the smallest unit suggested for TGR5 Y111A variants. Higher-order oligomers likely have a linear arrangement with interaction sites involving transmembrane helix 1 and helix 8 as well as transmembrane helix 5. The latter interaction is suggested to be disrupted by the Y111A mutation. The proposed model of TGR5 oligomer assembly broadens our view of possible oligomer patterns and affinities of class A GPCRs.

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“…According to our previous theoretical study 20 , it was observed that the binding site of TGR5 was formed by active site residues including Ser21, Asn76, Tyr89, Asn93, Ser157, Trp237, Tyr240 and Ser270. Thus, the grid was generated at the centroid point of the active site for consistency.…”

Section: Grid Generation and Ligand Preparationmentioning

confidence: 97%

Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening

Sindhu

Srinivasan

2015

Mol. BioSyst.

Self Cite

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Farnesoid X receptor and Takeda G-protein-coupled receptor-5 are well known bile acid receptors and act as promising targets for the drug development and treatment of diabetes. Agonists of both the bile acid receptors increase insulin sensitivity and control glucose, lipids and bile acid homeostasis. The current study deals with the identification of novel dual agonists using ligand and structure-based virtual screening. Initially, an experimentally proven well-known dual agonist of FXR and TGR5, namely INT-767, was docked into the binding sites of FXR and TGR5 to determine the protein residues important for ligand binding. The docked complexes FXRINT-767 and TGR5INT-767 were used to generate e-pharmacophore hypotheses. Ligand-based virtual screening was carried out using the hypothetical e-pharmacophore model against the ChemBridge database. Further, structure-based virtual screening was performed with screened hits to find potential agonists of FXR and TGR5. A total of four best agonists were identified based on their affinity and mode of interactions with the receptors. The binding mode of these compounds with both receptors was analyzed in detail. Furthermore, molecular dynamics, ADME toxicity prediction, density functional theory and binding free energy calculations were carried out to rank the compounds. Based on the above analyses, the most potent compound, ChemBridge_9149693, was selected for further in vitro studies. The results of in vitro assays suggested that ChemBridge_9149693 is a potent and promising drug for the treatment of type II diabetes. Thus, the compound could be used for further drug design and development of dual agonists of FXR and TGR5.

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Exploring the binding properties of agonists interacting with human TGR5 using structural modeling, molecular docking and dynamics simulations

Abstract: TGR5, act as a potential pharmacological target in the treatment of type II diabetes. In the computational study, structural modeling and binding site prediction of TGR5 receptor was performed. Two well-known agonists of TGR5 used to investigate the mode and mechanism of binding.

Cited by 37 publications

References 50 publications

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Structural assemblies of the di- and oligomeric G-protein coupled receptor TGR5 in live cells: an MFIS-FRET and integrative modelling study

Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening

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