This course aims to provide the student with the foundation of organic synthesis/medchem and analytical chemistry/NMR, i.e. what is useful for the rational design, synthesis and characterization of small molecules endowed with biological activity, i.e. what is particularly relevant for the pharmaceutical sector. The course will draw the student's attention to multi-disciplinary, chemistry-driven approaches to achieve a common goal - for this, the disciplines and techniques described in the course are often dealt with through different perspectives (for example, the use of NMR spectroscopy in the generation of target models and the structural optimization of small molecules, both considered both in terms of medchem and NMR technologies). As to organic synthesis/medchem-related topics, the course aims to provide the students with basic knowledge of pharmaceutical and medicinal chemistry and of its role in drug discovery, explaining how an organic chemist designs and selects molecules and reactions useful to support the identification and validation of molecular targets, to prepare drug-like collections of compounds for biological screening, and to structurally optimize biologically active compounds. The disciplines which can provide the medicinal chemist with elements for rational design and structural optimization of hits and leads of pharmaceutical value (i.e., computational chemistry, structural/biophysical sciences, etc.) are also presented in detail. Each of these topics is illustrated through the presentation and discussion of examples related to their application to modern successful pharmaceutical research / drug discovery projects. As to analyticals/NMR, the course aims to provide the basic knowledge of nuclear magnetic resonance (NMR) spectroscopy. The concepts necessary to make the student able to read mono and bidimensional NMR spectra of simple molecules will be introduced. The various NMR techniques recently developed for the study of biomolecules and in particular the information that the student will be able to obtain from the various spectroscopic techniques will therefore be presented in detail. Then the NMR techniques that can be used to study the interaction between a ligand molecule and the target macromolecule will be presented. These techniques can be based on the observation of ligand or receptor signals. Each topic will be illustrated through the presentation and discussion of examples.
Expected learning outcomes
At the end of the course, the student will know how organic chemistry, and in particular drug-like chemical diversity (assembled collections of different small organic molecules), can help in the identification and the characterization of new molecular targets; and will have acquired the necessary rudiments to understand the process of rational / computational design of small molecule modulators of either structurally characterized molecular targets (structure-based drug design, SBDD; fragment-based drug design, FBDD), or of non-structurally characterized molecular targets through their known ligands (ligand-based drug design, LBDD). Moreover, the student will acquire, besides the basic knowledge of NMR spectroscopy, also skills on different interaction techniques and learn how nuclear magnetic resonance can be important for the study of ligand-receptor interactions and for the development of new biologically active molecules.
- Chemical genetics in target ID and validation: elucidation of complex diseases mechanisms (cancer, neurodegeneration) using active compounds from phenotypic assays; identification and validation of druggable molecular targets and useful leads - bromodomains/inflammation, kinesin Eg5/cancer; - Rational design and structural optimization of biologically active compounds: basic principles of molecular modeling; molecular descriptors for in silico models of biologically active organic molecules; chemical and biological similarity; chemical diversity collections in drug discovery - rational design and optimization of HSP90 inhibitors; - Basic principles of Nuclear Magnetic Resonance: NMR signals, chemical shifts, influence of neighboring atoms, effect of bond electrons; nuclei equivalence and NMR signal intensity (chemical and magnetic equivalence of nuclei, dynamic processes, definition of spin system); spin-spin coupling (NMR signal multiplicity); 13C NMR spectroscopy (13C chemical shift and intensity, DEPT experiments); multiple summary exercises; - NMR determination of target-ligand interactions: Two-dimensional NMR spectroscopy (COSY, TOCSY, NOESY and HSQC spectra); NMR techniques to study the interactions between a small molecule (ligand, drug) and its receptor target (protein, DNA, RNA, membrane proteins); observation of macromolecule and ligand signals; multiple examples of applications of ligand-based techniques.
Prerequisites for admission
The student must know the fundamentals of chemistry and of organic chemistry (main organic compounds and reactions) in particular, through introductory chemistry courses of various BSc degrees. Basic notions of physics are also required.
Interactive frontal lessons, where students are encouraged to attend and to actively participate; discussions are fostered, to improve their critical evaluation skills, to assimilate the presented concepts and ideas, and to verify proper understanding. Presented materials will be made available through the ARIEL website. For each topic, one or more examples will be described, to show the potential of chemistry-supported approaches in biology, and in particular in pharmaceutical research. It is strongly recommended that students attend lectures.
P. Seneci. Chemical Sciences in Early Drug Discovery. Elsevier, Amsterdam, 2018. A. Randazzo. Guide to NMR spectral interpretation. A problem-based approach to determining the structures of small organic molecules. Loghia Publishing.
Assessment methods and Criteria
Learning assessment will involve a written exam at the end of the course, and a Group Seminar. Students attending the course can opt for a mid-term examination plus a second partial exam at the end of the course, splitting the two main topics - organic synthesis and analytical chemistry. The written exam includes open questions, chemical structures to be identified, charts and graphs to be completed; the earned mark will contribute to ≈70% of the total mark. Group Seminars will be delivered by teams of students, and will be evaluated looking at common (quality of ppt presentation, choice of presented papers) and individual parameters (individual presentations, answers to questions); the earned mark will contribute to ≈30% of the total mark.