DC5. Physicochemical profiling of macrocycles

Objectives

1. Measuring ionization, lipophilicity, polarity, chameleonicity and solubility descriptors to characterize the physicochemical profile of selected MCs from WP3
2. Build global and local lipophilicity predictors and local polarity, chameleonicity and solubility models
3. In depth analysis of chameleonicity data for drug design purposes.

Methodology

1. Potentiometry
2. Chromatographic methods based on different stationary/mobile phases combination
3. Shake-flask to measure thermodynamic solubility
4. Machine learning to build models
5. Molecular modeling tools for the implementation of chameleonicity in drug design

Expected Results

1. Dataset of experimental physicochemical data
2. Setting-up of lipophilicity calculators
3. Polarity, chameleonicity and solubility local predictors
4. Rules to apply chameleonicity in drug design; all specific for MCs

Planned secondment(s)

1. UU, M. Erdelyi, M16-M18: conformational studies by NMR to highlight chameleonic behavior
2. Roche, C. Kroll, M21-M24: extensive polarity determination
3. Selvita, S. Kostrun, M31-33: intracellular/lysosomal accumulation using Selvitas high-throughput imaging assay

Candidate profile

• Applicants should hold an MSc or equivalent in Chemical or Pharmaceutical sciences, with a preference for those who have a background in Medicinal Chemistry
• Prior experience with macrocycles and beyond-Rule-of-5 compounds is advantageous
• Scientific interest, dedication to research, and career goal to work in drug discovery
• Appreciation for interdisciplinarity and proactive drive to collaborate across fields
• Proficiency in English, good communication skill and social competence