DC4

Home institution: Lisbon University – Portugal (24 months)

Host institution: Wurzburg University - Germany (10 months)

PhD Enrolment #1: Lisbon University – Portugal

PhD Enrolment #2: Wurzburg University - Germany

Supervisor #1: Rita Guedes

Supervisor #2: Michael Decker

Intersectoral Secondment: Cyanagen – Italy

Objectives: The Laboratory of Computational Medicinal Chemistry, Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, University of Lisbon, Portugal, is looking to appoint a Marie Curie Research Fellow within a fixed term project entitled “Structure and ligand-based strategies to discover GPCR receptor modulators targeting the circadian clock and AD”, funded by the Horizon Europe project TClock4AD.

The doctoral candidate will work for two years in Portugal (Lisbon University) and for 10 months in Germany (University of Wurzburg) and will be involved in a 2-month secondment to an Italian company (Cyanagen).

The main objective of this DC is the discovery and optimization of small molecules targeting orexin receptor (OR) subtypes. An ultra-large virtual screening strategy will be developed for initial hit selection. The computer-aided drug design work will be conducted by two parallel approaches that will be compared and/or used in consensus to reach the best outcome. In the first approach, DC4 will: 1) design a chemical library (focusing on photoswitchable compounds and including DrugBank); 2) select and prepare the receptor structure; 3) assess docking performance; 4) perform a docking screening; 5) generate pharmacophore models, and screening; 6) filter the compounds by ADMET properties; 7) select compounds for experimental evaluation. In the second one, a workflow made up of molecular fingerprints, pocket similarity analysis/searching, and ML will be used to identify new compounds. Finally, hit-to-lead optimization (MD free energy calculations). Collaboration with DC2 is envisaged. @UNI WUERZBURG selected compounds will be synthesized according to newly established synthetic schemes, and affinity as well as intrinsic activities determined, in collaboration with DC11. The pharmacological and physicochemical data obtained will be used in feedback loops to refine improved ligands with high affinity and desired selectivity profiles.

Expected outcomes: The fellow is expected to generate breakthrough ideas in the assigned area of research, as well as to carry out research in line with the project plan. The fellow is also expected to contribute to dissemination and communication activities, besides actively collaborating within the TClock4AD network. This doctoral candidate will work closely with consortium partners at the University of Wuerzburg (Germany) and Cyanagen (Italy).