| 1. |
- Esguerra, Mauricio, et al.
(author)
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GPCR-ModSim : A comprehensive web based solution for modeling G-protein coupled receptors
- 2016
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In: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 44:W1, s. W455-W462
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Journal article (peer-reviewed)abstract
- GPCR-ModSim (http://open.gpcr-modsim.org) is a centralized and easy to use service dedicated to the structural modeling of G-protein Coupled Receptors (GPCRs). 3D molecular models can be generated from amino acid sequence by homology-modeling techniques, considering different receptor conformations. GPCR-ModSim includes a membrane insertion and molecular dynamics (MD) equilibration protocol, which can be used to refine the generated model or any GPCR structure uploaded to the server, including if desired non-protein elements such as orthosteric or allosteric ligands, structural waters or ions. We herein revise the main characteristics of GPCR-ModSim and present new functionalities. The templates used for homology modeling have been updated considering the latest structural data, with separate profile structural alignments built for inactive, partially-active and active groups of templates. We have also added the possibility to perform multiple-template homology modeling in a unique and flexible way. Finally, our new MD protocol considers a series of distance restraints derived from a recently identified conserved network of helical contacts, allowing for a smoother refinement of the generated models which is particularly advised when there is low homology to the available templates. GPCR- ModSim has been tested on the GPCR Dock 2013 competition with satisfactory results.
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| 2. |
- Gutiérrez-de-Terán, Hugo, et al.
(author)
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Structure-Based Rational Design of Adenosine Receptor Ligands
- 2017
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In: Current Topics in Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 1568-0266 .- 1873-4294. ; 17:1, s. 40-58
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Research review (peer-reviewed)abstract
- The family of adenosine receptors (ARs) is focus of several medicinal chemistry programs aimed to find new potent and selective drugs. Each receptor subtype has been proposed as a relevant drug target in the treatment of, e.g., cardiovascular or inflammatory diseases, asthma or Parkinson's disease. Until recently, most of these efforts have been dominated by ligand-based or empirical approaches. However, the latest advances in G protein-coupled receptor (GPCR) crystallography allowed for a thorough structural characterization of the A(2A)AR subtype, which has been crystalized with a number of agonists and antagonists. Consequently, the ligand discovery of AR ligands has been enriched with a number of structure-based approaches. These include the generation of higher-confident homology models for the remaining AR subtypes, virtual screening identification of novel chemotypes, structure-based lead-optimization programs, rationalization of selectivity profiles, or the structural characterization of novel binding sites that enable the design of novel allosteric modulators. Computational methodologies have importantly contributed to the success of these structure-based approaches, and the recent advances in the field are also analyzed in this review. We conclude that the design of adenosine receptor ligands has improved dramatically with the consideration of structure-based approaches, which is paving the way to a better understanding of the biology and pharmacological modulation of this relevant family of receptors.
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| 3. |
- Isaksson, Rebecka, et al.
(author)
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A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
- 2019
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In: ChemistryOpen. - : Wiley. - 2191-1363. ; 8:1, s. 114-125
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Journal article (peer-reviewed)abstract
- We here report on our continued studies of ligands binding tothe promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R ascompared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.
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| 4. |
- Rodriguez-Espigares, Ismael, et al.
(author)
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GPCRmd uncovers the dynamics of the 3D-GPCRome
- 2020
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In: Nature Methods. - : Springer Nature. - 1548-7091 .- 1548-7105. ; 17:8, s. 777-787
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Journal article (peer-reviewed)abstract
- G-protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new three-dimensional (3D) molecular structures of GPCRs (3D-GPCRome) over the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. Molecular dynamics (MD) simulations have become a widely established technique for exploring the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations require efficient storage resources and specialized software. Here we present GPCRmd (http://gpcrmd.org/), an online platform that incorporates web-based visualization capabilities as well as a comprehensive and user-friendly analysis toolbox that allows scientists from different disciplines to visualize, analyze and share GPCR MD data. GPCRmd originates from a community-driven effort to create an open, interactive and standardized database of GPCR MD simulations.
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| 5. |
- Sallander, Jessica, et al.
(author)
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Structural determinants of subtype selectivity and functional activity of angiotensin II receptors
- 2016
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In: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 26:4, s. 1355-1359
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Journal article (peer-reviewed)abstract
- Agonists of the angiotensin II receptor type 2 (AT(2)), a G-protein coupled receptor, promote tissue protective effects in cardiovascular and renal diseases, while antagonists reduce neuropathic pain. We here report detailed molecular models that explain the AT(2) receptor selectivity of our recent series of non-peptide ligands. In addition, minor structural changes of these ligands that provoke different functional activity are rationalized at a molecular level, and related to the selectivity for the different receptor conformations. These findings should pave the way to structure based drug discovery of AT(2) receptor ligands.
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| 6. |
- Vasile, Silvana, et al.
(author)
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Characterization of Ligand Binding to GPCRs Through Computational Methods
- 2018
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In: Computational Methods for GPCR Drug Discovery. - New York, NY : Humana Press. - 9781493974641 - 9781493984947 - 9781493974658 ; , s. 23-44
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Book chapter (peer-reviewed)abstract
- The recent increase in available G protein-coupled receptor structures now contributes decisively to the structure-based ligand design. In this context, computational approaches in combination with medicinal chemistry and pharmacology are extremely helpful. Here, we provide an update on our structure-based computational protocols, used to answer key questions related to GPCR-ligand binding. All combined, these techniques can shed light on ligand binding modes, determine the molecular basis of conformational selection, for agonists and antagonists, as well as of subtype selectivity. To illustrate each of these questions, we will consider examples from existing projects on three families of class A (rhodopsin-like) GPCRs: one small-molecule (nucleotide-like) family, i.e., the adenosine receptors, and two peptide-binding receptors: neuropeptide-Y and angiotensin II receptors. The successful application of the same computational protocols to investigate this diverse group of receptor families gives an idea of the general applicability of our methodology in the characterization of GPCR-ligand binding.
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| 7. |
- Vasile, Silvana, et al.
(author)
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Evolution of Angiotensin Peptides and Peptidomimetics as Angiotensin II Receptor Type 2 (AT2) Receptor Agonists
- 2020
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In: Biomolecules. - : MDPI AG. - 2218-273X. ; 10:4
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Journal article (peer-reviewed)abstract
- Angiotensin II receptor type 1 and 2 (AT1R and AT2R) are two G-protein coupled receptors that mediate most biological functions of the octapeptide Angiotensin II (Ang II). AT2R is upregulated upon tissue damage and its activation by selective AT2R agonists has become a promising approach in the search for new classes of pharmaceutical agents. We herein analyzed the chemical evolution of AT2R agonists starting from octapeptides, through shorter peptides and peptidomimetics to the first drug-like AT2R-selective agonist, C21, which is in Phase II clinical trials and aimed for idiopathic pulmonary fibrosis. Based on the recent crystal structures of AT1R and AT2R in complex with sarile, we identified a common binding model for a series of 11 selected AT2R agonists, consisting of peptides and peptidomimetics of different length, affinity towards AT2R and selectivity versus AT1R. Subsequent molecular dynamics simulations and free energy perturbation (FEP) calculations of binding affinities allowed the identification of the bioactive conformation and common pharmacophoric points, responsible for the key interactions with the receptor, which are maintained by the drug-like agonists. The results of this study should be helpful and facilitate the search for improved and even more potent AT2R-selective drug-like agonists.
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| 8. |
- Wannberg, Johan, et al.
(author)
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N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands
- 2024
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In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 265
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Journal article (peer-reviewed)abstract
- Two series of N-(heteroaryl)thiophene sulfonamides, encompassing either a methylene imidazole group or a tertbutylimidazolylacetyl group in the meta position of the benzene ring, have been synthesized. An AT(2)R selective ligand with a Ki of 42 nM was identified in the first series and in the second series, six AT(2)R selective ligands with significantly improved binding affinities and Ki values of <5 nM were discovered. The binding modes to AT(2)R were explored by docking calculations combined with molecular dynamics simulations. Although some of the high affinity ligands exhibited fair stability in human liver microsomes, comparable to that observed with C21 undergoing clinical trials, most ligands displayed a very low metabolic stability with t(1/2) of less than 10 min in human liver microsomes. The most promising ligand, with an AT(2)R K-i value of 4.9 nM and with intermediate stability in human hepatocytes (t(1/2) = 77 min) caused a concentration-dependent vasorelaxation of pre-contracted mouse aorta.
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