scholarly journals Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors

2020 ◽  
Vol 21 (24) ◽  
pp. 9728
Author(s):  
Katrin Denzinger ◽  
Trung Ngoc Nguyen ◽  
Theresa Noonan ◽  
Gerhard Wolber ◽  
Marcel Bermudez
Keyword(s):  
Therapeutic Potential ◽  
Binding Pocket ◽  
Docking Studies ◽  
General Mechanism ◽  
Extracellular Loop ◽  
Structure Based Drug Design ◽  
Loop Region ◽  
Biased Signaling ◽  
Dynamics Simulations ◽  
Ligand Bias

G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known β-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors.

scholarly journals Structural Insights into the Interaction of Filovirus Glycoproteins with the Endosomal Receptor Niemann-Pick C1: A Computational Study

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 913
Author(s):  
Manabu Igarashi ◽  
Takatsugu Hirokawa ◽  
Yoshihiro Takadate ◽  
Ayato Takada
Keyword(s):  
Receptor Binding ◽  
Ebola Virus ◽  
Computational Study ◽  
Binding Pocket ◽  
Crystal Structure Analysis ◽  
Receptor Binding Site ◽  
Structure Based Drug Design ◽  
Niemann Pick ◽  
Dynamics Simulations ◽  
Loop 2

Filoviruses, including marburgviruses and ebolaviruses, have a single transmembrane glycoprotein (GP) that facilitates their entry into cells. During entry, GP needs to be cleaved by host proteases to expose the receptor-binding site that binds to the endosomal receptor Niemann-Pick C1 (NPC1) protein. The crystal structure analysis of the cleaved GP (GPcl) of Ebola virus (EBOV) in complex with human NPC1 has demonstrated that NPC1 has two protruding loops (loops 1 and 2), which engage a hydrophobic pocket on the head of EBOV GPcl. However, the molecular interactions between NPC1 and the GPcl of other filoviruses remain unexplored. In the present study, we performed molecular modeling and molecular dynamics simulations of NPC1 complexed with GPcls of two ebolaviruses, EBOV and Sudan virus (SUDV), and one marburgvirus, Ravn virus (RAVV). Similar binding structures were observed in the GPcl–NPC1 complexes of EBOV and SUDV, which differed from that of RAVV. Specifically, in the RAVV GPcl–NPC1 complex, the tip of loop 2 was closer to the pocket edge comprising residues at positions 79–88 of GPcl; the root of loop 1 was predicted to interact with P116 and Q144 of GPcl. Furthermore, in the SUDV GPcl–NPC1 complex, the tip of loop 2 was slightly closer to the residue at position 141 than those in the EBOV and RAVV GPcl–NPC1 complexes. These structural differences may affect the size and/or shape of the receptor-binding pocket of GPcl. Our structural models could provide useful information for improving our understanding the differences in host preference among filoviruses as well as contributing to structure-based drug design.

scholarly journals Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1

2019 ◽  
Author(s):  
Shubhi Pandey ◽  
Xaria X. Li ◽  
Ashish Srivastava ◽  
Mithu Baidya ◽  
Punita Kumari ◽  
...  
Keyword(s):  
G Protein ◽  
Therapeutic Potential ◽  
Neutrophil Migration ◽  
Human Complement ◽  
Peptide Fragments ◽  
G Protein Coupling ◽  
Full Agonist ◽  
Protein Coupling ◽  
Biased Signaling ◽  
Ligand Bias

AbstractThe human complement component, C5a, binds two different seven transmembrane receptors termed as C5aR1 and C5aR2. C5aR1 is a prototypical G protein-coupled receptor that couples to Gαi sub-family of heterotrimeric G proteins and β-arrestins (βarr) following C5a stimulation. Peptide fragments derived from the carboxyl-terminus of C5a can still interact with the receptor, albeit with lower affinity, and can act as agonists or antagonists. However, whether such fragments might display ligand bias at C5aR1 remains unexplored. Here, we compare C5a and a modified C-terminal fragment of C5a, C5apep, in terms of G protein coupling, βarr recruitment, endocytosis and ERK1/2 MAP kinase activation at the human C5aR1. We discover that C5apep acts as a full-agonist for G protein coupling, while only displaying partial agonism for βarr recruitment. We also observe that whilst C5apep is significantly less efficient in inducing C5aR1 endocytosis compared to C5a, it exhibits robust activation of ERK1/2 phosphorylation at levels similar to C5a. Interestingly, C5apep displays full-agonist efficacy with respect to inhibiting LPS induced IL-6 secretion in human macrophages, but its ability to induce human neutrophil migration is substantially lower compared to C5a. Taken together, our findings reveal ligand-bias at C5aR1, not only with respect to transducer-coupling and receptor trafficking but also in terms of cellular responses. Our findings therefore establish a framework to explore additional levels of biased signaling and biased ligands at C5aR1 with therapeutic potential. More generally, our findings may be extended to discover biased ligands for the broad sub-family of chemokine GPCRs which also interact with chemokine ligands through a biphasic mechanism.

scholarly journals Molecular mechanism of biased signaling in a prototypical G protein–coupled receptor

Science ◽  
2020 ◽  
Vol 367 (6480) ◽  
pp. 881-887 ◽  
Author(s):  
Carl-Mikael Suomivuori ◽  
Naomi R. Latorraca ◽  
Laura M. Wingler ◽  
Stephan Eismann ◽  
Matthew C. King ◽  
...  
Keyword(s):  
G Protein ◽  
Protein A ◽  
Binding Pocket ◽  
Great Promise ◽  
G Protein Coupled Receptor ◽  
Structural Mechanism ◽  
Biased Signaling ◽  
Dynamics Simulations ◽  
Effective Drugs ◽  
G Protein Coupled

Biased signaling, in which different ligands that bind to the same G protein–coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.

scholarly journals Functional Characterization of the Dopaminergic Psychostimulant Sydnocarb as an Allosteric Modulator of the Human Dopamine Transporter

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 634
Author(s):  
Shaili Aggarwal ◽  
Mary Hongying Cheng ◽  
Joseph M. Salvino ◽  
Ivet Bahar ◽  
Ole Valente Mortensen
Keyword(s):  
Dopamine Transporter ◽  
Drugs Of Abuse ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Functional Characterization ◽  
Binding Pocket ◽  
Allosteric Site ◽  
Uptake Studies ◽  
Dynamics Simulations ◽  
A Site

The dopamine transporter (DAT) serves a critical role in controlling dopamine (DA)-mediated neurotransmission by regulating the clearance of DA from the synapse and extrasynaptic regions and thereby modulating DA action at postsynaptic DA receptors. Major drugs of abuse such as amphetamine and cocaine interact with DATs to alter their actions resulting in an enhancement in extracellular DA concentrations. We previously identified a novel allosteric site in the DAT and the related human serotonin transporter that lies outside the central orthosteric substrate- and cocaine-binding pocket. Here, we demonstrate that the dopaminergic psychostimulant sydnocarb is a ligand of this novel allosteric site. We identified the molecular determinants of the interaction between sydnocarb and DAT at the allosteric site using molecular dynamics simulations. Biochemical-substituted cysteine scanning accessibility experiments have supported the computational predictions by demonstrating the occurrence of specific interactions between sydnocarb and amino acids within the allosteric site. Functional dopamine uptake studies have further shown that sydnocarb is a noncompetitive inhibitor of DAT in accord with the involvement of a site different from the orthosteric site in binding this psychostimulant. Finally, DA uptake studies also demonstrate that sydnocarb affects the interaction of DAT with both cocaine and amphetamine. In summary, these studies further strengthen the prospect that allosteric modulation of DAT activity could have therapeutic potential.

scholarly journals The electrostatic allostery could be the trigger for the changes in dynamics for the PDZ domain of PICK1

2020 ◽  
Author(s):  
Amy O. Stevens ◽  
Yi He
Keyword(s):  
Surface Membrane ◽  
Pdz Domain ◽  
Binding Pocket ◽  
Pdz Domains ◽  
Interaction Domain ◽  
Bar Domain ◽  
Protein Protein Interaction ◽  
Loop Region ◽  
Key Factor ◽  
Dynamics Simulations

ABSTRACTThe PDZ domain is a highly abundant protein-protein interaction domain that exists in many signaling proteins, such as PICK1. Despite the highly conserved structure of the PDZ family, the PDZ family has an extremely low sequence identity, making each PDZ domain unique. PICK1 is the only protein in the human genome that is comprised of a PDZ domain and a BAR domain. PICK1 regulates surface membrane proteins and has been identified as an integral player in drug addiction. Like many PDZ-containing proteins, PICK1 is positively regulated by its PDZ domain and has thus drawn attention to be a potential drug target to curb the effects of substance abuse. The goal of this study is to use all-atom molecular dynamics simulations and the electrostatic analysis program, DelPhi, to better understand the unique interactions and dynamic changes in the PICK1 PDZ domain upon complex formation. Our results demonstrated that the PICK1 PDZ domain shares similar canonical PDZ-ligand hydrogen bonding networks and fluctuations of the carboxylate-binding loop to other PDZ domains. Furthermore, our results are unique to the PICK1 PDZ domain as we reveal that the binding of ligand opens up the binding pocket and, at the same time, reduces the fluctuations of both the central part of the binding pocket and the short loop region between the αA-helix and βC-strand. More importantly, the binding of ligand resulted in charge redistribution at the binding pocket region as well as the N- and C-termini of the PDZ domain that are not a part of the binding pocket. These results suggest that the electrostatic allostery resulted from ligand binding could be the key factor leading to the changes in dynamics which may be associated with the activation of PICK1. Based on these results, an effective drug to target PDZ domain must not only stably bind to the PICK1 PDZ domain but also prevent the electrostatic allostery of the PDZ domain.

scholarly journals Pharmacophore-Based Screening & Modification of Amiloride Analogs for targeting the NhaP-type Cation-Proton Antiporter in Vibrio cholerae

2021 ◽  
Author(s):  
Muntahi Mourin ◽  
Arittra Bhattacharjee ◽  
Alvan Wai ◽  
Georg Hausner ◽  
Joe O'Neil ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Vibrio Cholerae ◽  
Mutational Analysis ◽  
Md Simulations ◽  
Binding Pocket ◽  
Cation Binding ◽  
Important Amino Acid ◽  
Loop Region ◽  
Dynamics Simulations ◽  
Amiloride Analogs

Structural and mutational analysis of Vc-NhaP2 identified a putative cation binding pocket formed by antiparallel extended regions of two transmembrane segments (TMSs V/XII) along with TMS VI. Molecular Dynamics (MD) simulations suggested that the flexibility of TMS-V/XII is crucial for the intra-molecular conformational events in Vc-NhaP2. In this study, we developed some putative Vc-NhaP2 inhibitors from Amiloride analogs (AAs). Molecular docking of the modified AAs revealed promising binding. The four selected drugs potentially interacted with functionally important amino acid residues located on the cytoplasmic side of TMS VI, the extended chain region of TMS V and TMS XII and the loop region between TMSs VIIII and IX. Molecular dynamics simulations revealed that binding of the selected drugs can potentially destabilize the Vc-NhaP2 and alters the flexibility of the functionally important TMS VI. The work presents the utility of in silico approaches for the rational identification of potential targets and drugs that could target NhaP2 cation proton antiporter to control Vibrio cholerae. The goal is to identify potential drugs that can be validated in future experiments.

Lead Finding from Selected Flavonoids with Antiviral (SARS-CoV-2) Potentials against COVID-19: An in-silico Evaluation

2020 ◽  
Vol 23 ◽  
Author(s):  
Uma Sankar Gorla ◽  
GSN Koteswara Rao ◽  
Uma Sankar Kulandaivelu ◽  
Rajasekhar Reddy Alavala ◽  
Siva Prasad Panda
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Active Sites ◽  
Therapeutic Potential ◽  
Docking Studies ◽  
Biochanin A ◽  
High Morbidity ◽  
Structure Based Drug Design ◽  
Molecular Docking Studies ◽  
In Silico Molecular Docking

Background: COVID-19, a pandemic respiratory contagious viral (SARS-CoV-2) disease associated with high morbidity and mortality worldwide. Currently, there areno effective preventive or treatment strategies for COVID-19 and has been declared as a global health emergency by WHO. In silico molecular docking studies can be useful to predict the binding affinity between the phytocompound and the target protein and play a vital role in finding an inhibitor through structure-based drug design. Objective: In this aspect, our objective was to screen essential flavonoids against possible protein targets such as SARS-CoV-2 spike glycoprotein receptor binding domain (RBD-S) and host Angiotensin Converting Enzyme-2 protease domain (PD-ACE-2) using in silico molecular docking studies. Methods: Approximately 49 flavonoids were identified, evaluated for their drug likeness based on Lipinski rule, bioactivity scores, antiviral and toxicity profiles using SwissADME, Molinspiration, PASS and GUSAR online tools. The flavonoids that passed Lipinski rule were subjected to in silico analysis through molecular docking on RBD-S and PD-ACE-2 using Molegro Virtual Docker v6.0. Results: The bioactive flavonoids that showed NIL violations and found in compliance with Lipinski rule were selected for docking studies. In silicoanalysis reported that biochanin A and silymarin bind significantly at the active sites of RBD-Sand PD-ACE-2 with a MolDock score of -78.41and -121.28 kcal/mol respectively. Bioactivity scores, antiviral potential and tox-icity profiles were predicted for the top interacting phytocompounds and substantial relevant data was reported. Conclusion: The current outcomes created a new paradigm in understanding biochanin A and silymarin bioflavonoids as potent inhibitors of RBD-Sand PD-ACE-2 targets respectively, further work can be extended to confirm their therapeutic potential in COVID-19.

Use of Molecular Dynamics Simulations in Structure-Based Drug Discovery

2019 ◽  
Vol 25 (31) ◽  
pp. 3339-3349 ◽  
Author(s):  
Indrani Bera ◽  
Pavan V. Payghan
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Molecular Dynamics Simulations ◽  
Drug Target ◽  
Structural Information ◽  
Drug Binding ◽  
Structure Based Drug Design ◽  
Drug Designing ◽  
Target Binding ◽  
Dynamics Simulations

Background: Traditional drug discovery is a lengthy process which involves a huge amount of resources. Modern-day drug discovers various multidisciplinary approaches amongst which, computational ligand and structure-based drug designing methods contribute significantly. Structure-based drug designing techniques require the knowledge of structural information of drug target and drug-target complexes. Proper understanding of drug-target binding requires the flexibility of both ligand and receptor to be incorporated. Molecular docking refers to the static picture of the drug-target complex(es). Molecular dynamics, on the other hand, introduces flexibility to understand the drug binding process. Objective: The aim of the present study is to provide a systematic review on the usage of molecular dynamics simulations to aid the process of structure-based drug design. Method: This review discussed findings from various research articles and review papers on the use of molecular dynamics in drug discovery. All efforts highlight the practical grounds for which molecular dynamics simulations are used in drug designing program. In summary, various aspects of the use of molecular dynamics simulations that underline the basis of studying drug-target complexes were thoroughly explained. Results: This review is the result of reviewing more than a hundred papers. It summarizes various problems that use molecular dynamics simulations. Conclusion: The findings of this review highlight how molecular dynamics simulations have been successfully implemented to study the structure-function details of specific drug-target complexes. It also identifies the key areas such as stability of drug-target complexes, ligand binding kinetics and identification of allosteric sites which have been elucidated using molecular dynamics simulations.

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