scholarly journals A comprehensive evaluation of the potential binding poses of fentanyl and its analogs at the µ-opioid receptor

2021 ◽  
Author(s):  
Bing Xie ◽  
Alexander Goldberg ◽  
Lei Shi
Keyword(s):  
Opioid Receptor ◽  
Comprehensive Evaluation ◽  
Computational Study ◽  
Energy Landscape ◽  
Drug Market ◽  
Binding Pocket ◽  
Structural Basis ◽  
Binding Mechanism ◽  
Fentanyl Analogs ◽  
Dynamics Simulations

Fentanyl and its analogs are selective agonists of the µ-opioid receptor (MOR). Among novel synthetic opioids (NSOs), they dominate the recreational drug market and are the main culprits for the opioid crisis, which has been exacerbated by the COVID-19 pandemic. By taking advantage of the crystal structures of the MOR, several groups have investigated the binding mechanism of fentanyl, but have not reached a consensus, in terms of both the binding orientation and the fentanyl conformation. Thus, the binding mechanism of fentanyl at the MOR remains an unsolved and challenging question. Here, we carried out a systematic computational study to investigate the preferred fentanyl conformations, and how these conformations are being accommodated in the MOR binding pocket. We characterized the free energy landscape of fentanyl conformations with metadynamics simulations, as well as performed long-timescale molecular dynamics simulations to compare and evaluate several possible fentanyl binding conditions. Our results indicate that the most preferred binding pose in the MOR binding pocket corresponds well with the minima on the energy landscape of fentanyl in the absence of the receptor, while the energy landscape can be reconfigured by modifying the fentanyl scaffold. The interactions with the receptor may stabilize a slightly unfavored fentanyl conformation in an alternative binding pose. By extending similar investigations to fentanyl analogs, our findings establish a structure-activity relationship of fentanyl binding at the MOR. In addition to providing a structural basis to understand the potential toxicity of the emerging NSOs, such insights will contribute to developing new, safer analgesics.

scholarly journals Structural basis for ligand modulation of the CCR2 conformational landscape

2018 ◽  
Author(s):  
Bryn C. Taylor ◽  
Christopher T. Lee ◽  
Rommie E. Amaro
Keyword(s):  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Drug Targets ◽  
Control Cell ◽  
Binding Pocket ◽  
Drug Binding ◽  
Structural Basis ◽  
Cc Chemokine ◽  
Wide Range ◽  
Dynamics Simulations

AbstractCC Chemokine Receptor 2 (CCR2) is a part of the chemokine receptor family, an important class of therapeutic targets. These class A G-protein coupled receptors (GPCRs) are involved in mammalian signaling pathways and control cell migration toward endogenous CC chemokine ligands. Chemokine receptors and their associated ligands are involved in a wide range of diseases and thus have become important drug targets. Of particular interest is CCR2, which has been implicated in cancer, autoimmunity driven type-1 diabetes, diabetic nephropathy, multiple sclerosis, asthma, atherosclerosis, neuropathic pain, and rheumatoid arthritis. Although promising, CCR2 antagonists have been largely unsuccessful to date. Here, we investigate the effect of an orthosteric and an allosteric antagonist on CCR2 dynamics by coupling long timescale molecular dynamics simulations with Markov-state model theory. We find that the antagonists shift CCR2 into several stable inactive conformations that are distinct from the crystal structure conformation, and that they disrupt a continuous internal water and sodium ion pathway preventing transitions to an active-like state. Several of these stable conformations contain a putative drug binding pocket that may be amenable to targeting with another small molecule antagonist. In the absence of antagonists, the apo dynamics reveal intermediate conformations along the activation pathway that provide insight into the basal dynamics of CCR2, and may also be useful for future drug design.

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 Location of the hydrophobic pocket in the binding site of fentanyl analogs in the µ-opioid receptor

2007 ◽  
Vol 72 (7) ◽  
pp. 643-654
Author(s):  
Ljiljana Dosen-Micovic ◽  
Milovan Ivanovic ◽  
Vuk Micovic
Keyword(s):  
Opioid Receptor ◽  
Binding Pocket ◽  
Receptor Model ◽  
Hydrophobic Pocket ◽  
Optimal Position ◽  
Alkyl Groups ◽  
Fentanyl Analogs ◽  
Position And Orientation ◽  
Cis And Trans ◽  
Opioid Receptor Agonists

Fentanyl is a highly potent and clinically widely used narcotic analgesic. The synthesis of its analogs remains a challenge in an attempt to develop highly selective ?-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking of several specific fentanyl analogs to the ?-opioid receptor model, in order to test the hypothesis that the hydrophobic pocket accommodates alkyl groups at position 3 of the fentanyl skeleton, is described. The stereoisomers of the following compounds were studied: cis- and trans-3-methylfentanyl, 3,3-dimethylfentanyl, cis- and trans-3-ethylfentanyl, cis- and trans-3-propylfentanyl, cis-3-isopropylfentanyl and cis-3-benzylfentanyl. The optimal position and orientation of these fentanyl analogs in the binding pocket of the ?-receptor, explaining their enantiospecific potency, were determined. It was found that the 3-alkyl group of cis-3R,4S and trans-3S,4S stereoisomers of all the active compounds occupies the hydrophobic pocket between TM5, TM6 and TM7, made up of the amino acids Trp318 (TM7), Ile322 (TM7), Ile301 (TM6) and Phe237 (TM5). However, the fact that this hydrophobic pocket can also accommodate the bulky 3-alkyl substituents of the two inactive compounds: cis-3-isopropylfentanyl, and cis-3-benzylfentanyl, indicates that this hydrophobic pocket in the employed receptor model is probably too large. .

Probing the binding mechanism of novel dual NF-κB/AP-1 inhibitors by 3D-QSAR, docking and molecular dynamics simulations

RSC Advances ◽  
2015 ◽  
Vol 5 (99) ◽  
pp. 81523-81532 ◽  
Author(s):  
Shaojie Ma ◽  
Shepei Tan ◽  
Danqing Fang ◽  
Rong Zhang ◽  
Shengfu Zhou ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Sites ◽  
Computational Study ◽  
3D Qsar ◽  
Structural Features ◽  
Binding Mechanism ◽  
Interaction Mechanisms ◽  
Dynamics Simulations

Potent dual NF-κB/AP-1 inhibitors could effectively treat immunoinflammatory diseases. An integrated computational study was carried out to identify the most favourable binding sites, the structural features and the interaction mechanisms.

scholarly journals Structural basis for binding mechanism of human serum albumin complexed with cyclic peptide dalbavancin

2020 ◽  
Author(s):  
Sho Ito ◽  
Akinobu Senoo ◽  
Satoru Nagatoishi ◽  
Masahito Ohue ◽  
Masaki Yamamoto ◽  
...  
Keyword(s):  
Human Serum Albumin ◽  
Serum Albumin ◽  
Human Serum ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Binding Pocket ◽  
Structural Features ◽  
Structural Basis ◽  
Binding Mechanism ◽  
Loop Region

ABSTRACTCyclic peptides, with unique structural features, have emerged as new candidates for drug discovery; their association with human serum albumin (HSA; long blood half-life), is crucial to improve drug delivery and avoid renal clearance. Here, we present the crystal structure of HSA complexed with dalbavancin, a clinically used cyclic peptide. SAXS and ITC experiments showed that the HSA-dalbavancin complex exists in a monomeric state; dalbavancin is only bound to the subdomain IA of HSA in solution. Structural analysis and MD simulation revealed that the swing of Phe70 and movement of the helix near dalbavancin were necessary for binding. The flip of Leu251 promoted the formation of the binding pocket with an induced-fit mechanism; moreover, the movement of the loop region including Glu60 increased the number of non-covalent interactions with HSA. These findings may support the development of new cyclic peptides for clinical use, particularly the elucidation of their binding mechanism to HSA.

scholarly journals Conformational flexibility of GRASP protein and its constituent PDZ subdomains reveals structural basis of its promiscuous interactome

2019 ◽  
Author(s):  
Luis Felipe S. Mendes ◽  
Mariana R. B. Batista ◽  
Peter J. Judge ◽  
Anthony Watts ◽  
Christina Redfield ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Secretory Pathway ◽  
Binding Pocket ◽  
Conformational Space ◽  
Structural Basis ◽  
Central Component ◽  
Pdz Domains ◽  
Multiple Partners ◽  
Binding Partners ◽  
Dynamics Simulations

AbstractThe Golgi complex is a central component of the secretory pathway, responsible for several critical cellular functions in eukaryotes. The complex is organized by the Golgi matrix, which includes the Golgi Reassembly and Stacking Proteins (GRASPs), which participate in cisternae stacking and lateral linkage in vertebrates. GRASPs also have critical roles in other processes, with an unusual ability to interact with several different protein binding partners. The conserved N-terminus of the GRASP family includes two PDZ domains. Previous crystallographic studies of orthologues suggest that PDZ1 and PDZ2 have similar conformations and secondary structure content, however PDZ1 alone mediates nearly all the interactions between GRASPs and their binding partners. In this work, NMR, Synchrotron-Radiation Circular Dichroism and Molecular Dynamics were used to examine the structure, flexibility and stability of the two constituent PDZ domains. GRASP PDZs are structured in an unusual β3α1β4β5α2β6β1β2 secondary structural arrangement and NMR data indicates that the PDZ1 binding pocket is formed by a stable β2-strand and a more flexible and unstable α2-helix, suggesting an explanation for the higher PDZ1 promiscuity. The conformational free energy profiles of the two PDZ domains were calculated using Molecular Dynamics simulations. The data suggest that, after binding, the protein partner significantly reduces the conformational space that GRASPs can access by stabilizing one particular conformation, in a partner-dependent fashion. The structural flexibility of PDZ1, modulated by PDZ2, and the coupled, coordinated movement between the two PDZs enable GRASPs to interact with multiple partners, allowing them to function as promiscuous, multitasking proteins.Significance StatementGolgi Reassembly and Stacking Proteins (GRASPs) play pivotal roles in the maintenance of Golgi structure as well as in unconventional protein secretion. Their broad network of interactions is mainly sustained by the two-PDZ domains located in the N-terminal portion of the protein. The asymmetry of the PDZ domains in terms of number and diversity of interacting partners has been long recognized, but the molecular determinants of that asymmetry remains largely unknown. The biophysical data presented here provide a firm basis for understanding why PDZ1 behaves differently to PDZ2 in solution, despite their similar 3D structures. Furthermore, we propose that PDZ2 assist ligand binding to PDZ1, by means of conformational stabilization.

scholarly journals Insights Into the Binding Mechanism of GC7 to Deoxyhypusine Synthase in Sulfolobus solfataricus: A Thermophilic Model for the Design of New Hypusination Inhibitors

2020 ◽  
Vol 8 ◽  
Author(s):  
Mattia D'Agostino ◽  
Stefano Motta ◽  
Alice Romagnoli ◽  
Patrick Orlando ◽  
Luca Tiano ◽  
...  
Keyword(s):  
Specific Binding ◽  
Sulfolobus Solfataricus ◽  
Binding Pocket ◽  
Cellular Growth ◽  
Binding Mechanism ◽  
Post Translational Modification ◽  
Deoxyhypusine Synthase ◽  
Deoxyhypusine Hydroxylase ◽  
Dynamics Simulations ◽  
Polypeptide Chains

Translation factor 5A (eIF5A) is one of the most conserved proteins involved in protein synthesis. It plays a key role during the elongation of polypeptide chains, and its activity is critically dependent on hypusination, a post-translational modification of a specific lysine residue through two consecutive enzymatic steps carried out by deoxyhypusine synthase (DHS), with spermidine as substrate, and deoxyhypusine hydroxylase (DOHH). It is well-established that eIF5A is overexpressed in several cancer types, and it is involved in various diseases such as HIV-1 infection, malaria, and diabetes; therefore, the development of inhibitors targeting both steps of the hypusination process is considered a promising and challenging therapeutic strategy. One of the most efficient inhibitors of the hypusination process is the spermidine analog N1-guanyl-1,7-diaminoheptane (GC7). GC7 interacts in a specific binding pocket of the DHS completely blocking its activity; however, its therapeutic use is limited by poor selectivity and restricted bioavailability. Here we have performed a comparative study between human DHS (hDHS) and archaeal DHS from crenarchaeon Sulfolobus solfataricus (aDHS) to understand the structural and dynamical features of the GC7 inhibition. The advanced metadynamics (MetaD) classical molecular dynamics simulations show that the GC7 interaction is less stable in the thermophilic enzyme compared to hDHS that could underlie a lower inhibitory capacity of the hypusination process in Sulfolobus solfataricus. To confirm this hypothesis, we have tested GC7 activity on S. solfataricus by measuring cellular growth, and results have shown the lack of inhibition of aIF5A hypusination in contrast to the established effect on eukaryotic cellular growth. These results provide, for the first time, detailed molecular insights into the binding mechanism of GC7 to aDHS generating the basis for the design of new and more specific DHS inhibitors.

Bonded Force Constant Derivation of Lysine-Arginine Cross-linked Advanced Glycation End-Products

2018 ◽  
Author(s):  
Anthony Nash ◽  
Nora H de Leeuw ◽  
Helen L Birch
Keyword(s):  
Molecular Dynamics ◽  
Force Constant ◽  
Computational Study ◽  
Force Constants ◽  
Quantum Mechanical ◽  
Advanced Glycation ◽  
Partial Charges ◽  
Cross Links ◽  
Complete Set ◽  
Dynamics Simulations

<div> <div> <div> <p>The computational study of advanced glycation end-product cross- links remains largely unexplored given the limited availability of bonded force constants and equilibrium values for molecular dynamics force fields. In this article, we present the bonded force constants, atomic partial charges and equilibrium values of the arginine-lysine cross-links DOGDIC, GODIC and MODIC. The Hessian was derived from a series of <i>ab initio</i> quantum mechanical electronic structure calculations and from which a complete set of force constant and equilibrium values were generated using our publicly available software, ForceGen. Short <i>in vacuo</i> molecular dynamics simulations were performed to validate their implementation against quantum mechanical frequency calculations. </p> </div> </div> </div>

Structural Insights into Azole-based Inhibitors of Heme Oxygenase-1: Development of Selective Compounds for Therapeutic Applications

2019 ◽  
Vol 25 (42) ◽  
pp. 5803-5821 ◽  
Author(s):  
Mona N. Rahman ◽  
Dragic Vukomanovic ◽  
Jason Z. Vlahakis ◽  
Walter A. Szarek ◽  
Kanji Nakatsu ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Competitive Inhibition ◽  
Cytochromes P450 ◽  
Structural Similarity ◽  
Binding Pocket ◽  
Initial Study ◽  
Structural Basis ◽  
Heme Oxygenase 1 ◽  
Design Strategies ◽  
Inhibitor Binding

The development of isozyme-selective heme oxygenase (HO) inhibitors promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties with a role in several disease states; thus, it is an enticing therapeutic target. Historically, the metalloporphyrins have been used as competitive HO inhibitors based on their structural similarity to the substrate, heme. However, heme’s important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), results in non-selectivity being an unfortunate side effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort over a decade ago to develop novel compounds as potent, selective inhibitors of HO. The result was the creation of the first generation of non-porphyrin based, non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated and provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies. Notably, HO-1 inhibitors are of particular interest for the treatment of hyperbilirubinemia and certain types of cancer. Key features based on this initial study have already been used by others to discover additional potential HO-1 inhibitors. Moreover, studies have begun to use selected compounds and determine their effects in some disease models.

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