The posting
Discover and optimise novel drug candidates targeting GPRC5B, an emerging therapeutic target in leukodystrophy. Combine AI-assisted virtual screening, molecular modelling and experimental validation to uncover new treatment strategies for these rare neurological diseases. POLARIS doctoral network POLARIS is a European Marie Skłodowska-Curie Doctoral Network focused on accelerating therapy development for leukodystrophies: rare genetic disorders affecting the brain’s white matter. The network aims to strengthen the full translational pathway, from understanding disease mechanisms and developing disease models to preclinical therapy testing, clinical readiness and patient-informed treatment priorities. To achieve this, POLARIS brings together expertise in leukodystrophy biology, advanced disease models, therapeutic innovation, biomarker development, clinical translation, patient engagement, and ethical, regulatory and health-economic aspects of therapy development. The network will train a cohort of doctoral candidates in an international and interdisciplinary environment, combining academic research, industry-based preclinical development, secondments, network-wide training and transferable-skills development. For this position, the PhD project will be conducted at two institutions in Barcelona, Spain: the Hospital del Mar Research Institute (HMRIB) and the University of Barcelona, in collaboration with the Bellvitge Biomedical Research Institute (IDIBELL). Academic supervision and disease-specific expertise will be provided by Dr Jana Selent at HMRIB and Dr Raul Estévez at the University of Barcelona–IDIBELL. You will focus on the discovery, optimisation and functional characterisation of novel GPRC5B modulators through an integrated computational and experimental drug discovery strategy. GPRC5B is an orphan G protein-coupled receptor implicated in leukodystrophy pathogenesis and brain homeostasis. It represents a promising but insufficiently explored therapeutic
target. Your research will combine computational and experimental approaches to: Identify novel GPRC5B modulators using AI-based virtual screening, structural modelling and bioinformatics across large chemical libraries. Prioritise and optimise candidate compounds by integrating predicted binding modes, structural features and compound properties. Investigate disease-associated GPRC5B variants and their potential effects on receptor structure, function and molecular interactions, supporting mechanistic interpretation and experimental design. Validate and characterise candidate compounds using cell-based pharmacological and biochemical assays, including assessment of potency, selectivity, receptor signalling and constitutive activity. Perform structure–activity relationship (SAR) studies to guide the optimisation of promising chemical series. Investigate the functional effects of patient-associated GPRC5B variants on receptor expression, trafficking, signalling and protein interactions. Study the relationship between GPRC5B and MLC1 to further understand their potential role in leukodystrophy. Test optimised compounds in disease-relevant cellular models, including patient-derived astrocytes. As part of the POLARIS training programme, you will undertake two planned secondments: A three-month secondment at ENAMINE in year 2, where you will gain experience in SAR design, compound synthesis and quality-control workflows. A three-month secondment at Istituto Superiore di Sanità in year 3, focusing on phenotypic testing in patient-derived astrocytes. The project will provide interdisciplinary training in AI-enabled computational drug discovery, molecular pharmacology, medicinal chemistry and translational neuroscience. The aim is to deliver experimentally validated and optimised GPRC5B chemical tools while advancing our understanding of GPRC5B biology in leukodystrophy. We are looking for a motivated candidate with a strong interest in interdisciplinary drug discov
