Dynamic pharmacophores for the discovery of specific modulators of G protein-coupled receptors.

• Applicant: Professor Dr. Marcel Bermudez
• Subject Area: Pharmacy
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407626949

• Final Report Year: 2023

Final Report Abstract

G protein-coupled receptors represent complex and dynamic drug targets with a broad range of possible functional outcomes. Binding of a specific ligand can induce or stabilize a certain receptor conformation which is typically linked to the pharmacological outcome of that ligand. Despite huge advances in GPCR research over the last decades, it still remains elusive how the functional complexity is orchestrated. A prominent example is biased signalling, a phenomenon that is characterized by a shift in the naturally imprinted signalling profile of a receptor. Our major aim was to understand the complexity of GPCR functions and the mechanisms underlying ligand-dependent effects such as biased signalling. Therefore, we used a fully automated combination of three-dimensional pharmacophore models and molecular dynamics simulations. We call this approach ’dynamic pharmacophores’, because it provides information on the interaction pattern in spatiotemporal context. These dynamic pharmacophores carry much more information than static models and could be used to unveil distinct receptor functions, even if they result from subtle conformational changes. We have applied this approach on different receptors including muscarinic and opioid receptors, and studied several functional outcomes such as partial receptor activation, or biased signalling. We provide mechanistic explanations on how ligands unfold their specific pharmacological characteristics and we have used this knowledge to identify novel GPCR modulators with distinct functionality. Key results from these studies are a generalizable mechanism by which one can design biased ligands for aminergic GPCRs by interfering with the closure of the extracellular binding site during receptor activation. Another key result is the identification of the first M3 selective agonists that might be useful to control insulin secretion.

Publications

• BiasDB: A Comprehensive Database for Biased GPCR Ligands. Cold Spring Harbor Laboratory.
  Omieczynski, Christian; Nguyen, Trung Ngoc; Sribar, Dora; Deng, Lihua; Stepanov, Dmitri; Schaller, David; Wolber, Gerhard & Bermudez, Marcel
  
• Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors. International Journal of Molecular Sciences, 21(24), 9728.
  Denzinger, Katrin; Nguyen, Trung Ngoc; Noonan, Theresa; Wolber, Gerhard & Bermudez, Marcel
  
• Ligand-Specific Allosteric Coupling Controls G-Protein-Coupled Receptor Signaling. ACS Pharmacology & Translational Science, 3(5), 859-867.
  Holze, Janine; Bermudez, Marcel; Pfeil, Eva Marie; Kauk, Michael; Bödefeld, Theresa; Irmen, Matthias; Matera, Carlo; Dallanoce, Clelia; De Amici, Marco; Holzgrabe, Ulrike; König, Gabriele Maria; Tränkle, Christian; Wolber, Gerhard; Schrage, Ramona; Mohr, Klaus; Hoffmann, Carsten; Kostenis, Evi & Bock, Andreas
  
• Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor. Molecules, 25(9), 2087.
  Dumitrascuta, Maria; Bermudez, Marcel; Ballet, Steven; Wolber, Gerhard & Spetea, Mariana
  
• N-Phenethyl Substitution in 14-Methoxy-N-methylmorphinan-6-ones Turns Selective µ Opioid Receptor Ligands into Dual µ/δ Opioid Receptor Agonists. Scientific Reports, 10(1).
  Dumitrascuta, Maria; Bermudez, Marcel; Ben, Haddou Tanila; Guerrieri, Elena; Schläfer, Lea; Ritsch, Andreas; Hosztafi, Sandor; Lantero, Aquilino; Kreutz, Christoph; Massotte, Dominique; Schmidhammer, Helmut; Wolber, Gerhard & Spetea, Mariana
  
• Next generation 3D pharmacophore modeling. WIREs Computational Molecular Science, 10(4).
  Schaller, David; Šribar, Dora; Noonan, Theresa; Deng, Lihua; Nguyen, Trung Ngoc; Pach, Szymon; Machalz, David; Bermudez, Marcel & Wolber, Gerhard
  
• The Role of Orthosteric Building Blocks of Bitopic Ligands for Muscarinic M1 Receptors. ACS Omega, 5(49), 31706-31715.
  Volpato, Daniela; Kauk, Michael; Messerer, Regina; Bermudez, Marcel; Wolber, Gerhard; Bock, Andreas; Hoffmann, Carsten & Holzgrabe, Ulrike
  
• Allosteric coupling and biased agonism in G protein‐coupled receptors. The FEBS Journal, 288(8), 2513-2528.
  Bock, Andreas & Bermudez, Marcel
  
• Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain without Rewarding Effects in Mice: An Experimental Assessment and Molecular Docking. Molecules, 26(11), 3267.
  Dumitrascuta, Maria; Bermudez, Marcel; Trovato, Olga; De Neve, Jolien; Ballet, Steven; Wolber, Gerhard & Spetea, Mariana
  
• Structure‐based identification of dual ligands at the A2AR and PDE10A with anti‐proliferative effects in lung cancer cell‐lines. Journal of Cheminformatics, 13(1).
  Kalash, Leen; Winfield, Ian; Safitri, Dewi; Bermudez, Marcel; Carvalho, Sabrina; Glen, Robert; Ladds, Graham & Bender, Andreas
  
• Community guidelines for GPCR ligand bias: IUPHAR review 32. British Journal of Pharmacology, 179(14), 3651-3674.
  Kolb, Peter; Kenakin, Terry; Alexander, Stephen P. H.; Bermudez, Marcel; Bohn, Laura M.; Breinholt, Christian S.; Bouvier, Michel; Hill, Stephen J.; Kostenis, Evi; Martemyanov, Kirill A.; Neubig, Rick R.; Onaran, H. Ongun; Rajagopal, Sudarshan; Roth, Bryan L.; Selent, Jana; Shukla, Arun K.; Sommer, Martha E. & Gloriam, David E.
  
• Hybridization into a Bitopic Ligand Increased Muscarinic Receptor Activation for Isopilocarpine but Not for Pilocarpine Derivatives. Journal of Natural Products, 86(4), 869-881.
  Heinz, Christine S.; Bermudez, Marcel; Jaiswal, Natasha; Große, Carolin; Kauk, Michael; Hoffmann, Carsten & Holzgrabe, Ulrike