This course will cover the following topics, which will be also discussed through case studies and evaluation of scientific publications, focusing on research methodology.  

- Chemical aspects of drug metabolism: introduction, effects of chemical structure on Phase I oxidative, reductive, and hydrolytic reactions, effects of chemical structure on phase II conjugative reactions (COMT and PNMT-catalyzed methylation, acetylation, sulfation, glucuronidation, amino acid conjugation, mercapturic acid formation), sites of metabolism, metabolic pathways of selected common drugs.

- Hit identification: overview of the drug discovery process; target-based, systems-based and chemocentric drug discovery; de novo drug design vs screening (virtual screening, random screening, high throughput screening); guiding principles and challenges in target-based and phenotypic drug discovery; chemical probes; compound sources for chemical libraries and focused compound collections; fragment-based drug discovery (principles, fragment-based screening, fragment elaboration, fragment-based approved drugs); drug repositioning (principles and challenges, case studies); biological products; innovative chemical modalities for challenging targets: undruggable targets and multispecific drugs (sequentially obligate multispecific drugs, matchmakers, PROTAC). Hit triage and prioritization: physicochemical and substructure filters; PAINS.

- Hit-to-lead development: challenges and objectives; multiparameter optimization; structure-activity relationship; bioisosterism and non-classical isosteres; SAR studies, structure modification strategies and application rules for hit expansion.

- Lead optimization: progression criteria and drug candidate parameters; lead optimization screening plan; main strategies to increase drug-likeness; case studies.