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Mechanisms of Disease

Molecular Pharmacology of G protein-coupled receptors (MolPharmGPCR)

Marián Castro
Group Leader | Associate Professor
marian.castro@usc.es
 
Lab: PSSL2
Field of knowledge

G protein-coupled receptors (GPCRs) constitute a principal family of therapeutic targets in many disease areas. We study specific members of this receptor family with the aim of deciphering novel aspects of their pharmacology and signalling that could potentially lead to improved therapies. We focus on GPCRs that constitute well-validated therapeutic targets in diseases with unmet medical need, as well as on poorly explored GPCRs that emerge as of potential physio-pathologically relevance, with particular interest in Central Nervous System diseases.
 

Among our specific aims are to identify and characterize small-molecule ligands and mechanisms of action for pharmacological modulation of GPCR function leading to specific cellular responses. We carry out in vitro and cell-based pharmacological assays involving biochemistry, cell and molecular biology, and biomolecular imaging techniques. Much of our research is done in collaboration with biocomputational and medicinal chemistry groups. Our final goal is to advance the knowledge in the field of GPCR pharmacology to open pads to more efficacious and safer drugs targeting this receptor family.

Research Lines

  • Investigation of novel mechanisms of pharmacological modulation of GPCR function such as allosterism and biased signalling. We carried out this research particularly on targets on which the group accumulates expertise, and for which we can count on medicinal chemistry and structural support. We believe the exploration of new aspects of GPCR pharmacology not exploited by current drugs might result therapeutically advantageous both on emerging as well as on well-validated, historical GPCR therapeutic targets.
     
  • Elucidation of components of the intracellular signalling of GPCRs leading to specific cell response, and potentially susceptible of selective pharmacological modulation. We aim at integrating basic and molecular pharmacological findings into the context of specific cellular responses. For this we study aspects of intracellular signalling such as kinetics and subcellular location with temporal and spatial resolution using biosensors/imaging and disruption strategies among other approaches.
     
  • Sustained surveillance on potential innovative GPCR targets in areas of unmet medical need. We undertake basic research on emerging targets combined with expansion of their small-molecule pharmacology toolbox to gather knowledge and provide pharmacological probes for speeding up target validation/valorisation.

Members

 

Alba Paz Castro
PhD student

Selected publications

Allosteric modulation of dopamine D2L receptor in complex with Gi1 and Gi2 proteins: the effect of subtle structural and stereochemical ligand modifications

Żuk, J. , Bartuzi, D. , Silva, A.G. , Pitucha, M. , Koszła, O. , Wróbel, T.M., Matosiuk, D., Castro, M. , Kaczor, A.A.

Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder

Enza Lacivita, Mauro Niso, Margherita Mastromarino, Andrea Garcia Silva, Cibell Resch, Andre Zeug, María I. Loza, Marián Castro, Evgeni Ponimaskin, and Marcello Leopoldo

Synthesis, pharmacological and structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs

Kondej, Magda; Wrobel, Tomasz M.; Silva, Andrea G.; Stepnicki, Piotr; Koszla, Oliwia; Kedzierska, Ewa; Bartyzel, Agata; Biala, Grazyna; Matosiuk, Dariusz; Loza, Maria I.; Castro, Marian; Kaczor, Agnieszka A.
Development of Fluorescent Probes that Target Serotonin 5-HT2B Receptors
Azuaje, J; Lopez, P; Iglesias, A; de la Fuente, RA; Perez-Rubio, JM; Garcia, D; Stepniewski, TM; Garcia-Mera, X; Brea, JM; Selent, J; Perez, D; Castro, M; Loza, MI; Sotelo, E
Distinct phosphorylation sites on the ghrelin receptor, GHSR1a, establish a code that determines the functions of ß-arrestins.
Bouzo-Lorenzo M, Santo-Zas I, Lodeiro M, Nogueiras R, Casanueva FF, Castro M, Pazos Y, Tobin AB, Butcher AJ, Camiña JP.

Ligand Residence Time at G-protein-Coupled Receptors-Why We Should Take Our Time To Study It

Hoffmann C, Castro M, Rinken A, Leurs R, Hill SJ, Vischer HF.

Selected Results

Projects

National project(s)

Development of a first-in-class targeted therapy for metastatic NSCLC
REF: LABAE211721DELADuration: -
PI: María de la Fuente Freire
Fundación Científica AECC. PROYECTOS AECC Lab.
Biología de membranas y mecanismos de transducción de señales en farmacología aplicada
REF: ED431CDuration: -
PI: María Isabel Loza García
CONSELLERIA DE CULTURA, EDUCACION E UNIVERSIDADE
Farmacología del receptor de fractalquina CX3CR1: identificación de ligandos novedosos y descifrado de su señalización intracelular espaciotemporal - GENERACIÓN DE CONOCIMIENTO 2020
REF: PID2020-119754GB-I00Duration: -
PI: María de los Ángeles Castro Pérez
AGENCIA ESTATAL DE INVESTIGACION

Alliances

European Research Network on Signal Transduction (ERNEST)

Patents

Derivatives of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, the method of their preparation and their application
Aplication Nº: PL430108A1
Agnieszka Anna Kaczor, Magda Kondej, Tomasz M. Wróbel, Piotr Stępnicki, Dariusz Matosiuk, María De Los Ángeles Castro Pérez, Andrea García Silva, María Isabel Loza García
N-[ω-(4-substituted-piperazin-1-yl)alkyl]-1H-indazole-3-carboxamide derivatives, method of their preparation and their application
Aplication Nº: PL43826221A
Agnieszka Anna Kaczor; Piotr Stępnicki; Tomasz Wróbel; Dariusz Matosiuk; María de los Ángeles Castro Pérez; María Isabel Loza García; Martyna Z. Wróbel; Andrzej Chodkowski; Jadwiga Turło