Master Project
PIs : Giovanni D’Angelo (UPDANGELO’s lab) and Matteo Dal Peraro (LBM lab)
Starting date: as soon as possible
Background
The ceramide transfer protein (CERT, encoded by CERT1) mediates non-vesicular transfer of ceramide from the endoplasmic reticulum to the Golgi, a crucial step in sphingolipid metabolism. Mutations in CERT1 have been linked to a rare neurodevelopmental disorder, known as CerTra, which is caused by hyperactive forms of CERT that disrupt lipid homeostasis and lead to excess sphingomyelin production. Targeting CERT with small-molecule inhibitors offers a promising therapeutic strategy with both pharmacological and medical relevance.
Aim
This Master’s project aims to conduct an in silico screen of a large compound library (over 100,000 molecules) to identify inhibitors of CERT. The focus will be on docking compounds to different functional domains of CERT, such as the START domain (which binds ceramide), the PH domain (which interacts with Golgi lipids), and regulatory regions. Special attention will also be given to how disease-associated mutations may alter binding sites and influence druggability.
Methods
The project will employ state-of-the-art molecular docking approaches in combination with modern AI and machine learning methods for compound scoring, clustering, and ADMET prediction. This will allow prioritization of structurally diverse compounds with favorable pharmacological properties. Computational modeling of mutant CERT proteins will also be performed to assess potential differences in compound binding compared to the wild-type protein.
Expected Outcomes
The study will generate a prioritized list of candidate inhibitors with high predicted binding affinity and promising drug-like properties. These compounds will form the basis for subsequent experimental validation in cellular assays and, eventually, in animal models of CerTra. Beyond identifying potential therapeutic leads, the project will also provide new insights into CERT structure-function relationships and the molecular basis of disease-causing mutations.
For more information:
https://www.epfl.ch/labs/dangelo-lab/
https://www.epfl.ch/labs/lbm/
Please send us a CV and motivation letter to [email protected]