Chemical Physics Methods for Investigating Molecular Structure (3 CFU)
- Non-covalent interactions underlying the folding process (short-range repulsions, van der Waals and electrostatic interactions, hydrogen bonds, stacking and hydrophobic interactions)
- Molecular mechanics (basics). Force field, modelling of bonding and non-bonding interactions, structure optimization. Molecular dynamics (short introduction).
- Mass spectrometry. Single focusing mass spectrometer. Magnetic analyzer. Time-of-flight analyzer. Fragmentation spectra.
- Introduction to crystallography. Point groups, space groups. Generation of X-rays. Synchrotron light sources. Real lattice, reciprocal lattice. Bragg Law, structure factor. Phase problem and its solution for biological polymers.
NMR spectroscopy (1 CFU)
- Nuclear Magnetic Resonance spectroscopy:
- One-dimensional 1H-NMR experiments: chemical shift and coupling constants,
- Two-dimensional NMR spectroscopy: preparation, evolution and mixing, data acquisition and graphical representation. Homonuclear (H,H) correlated NMR spectroscopy: COSY,
- The nuclear Overhauser effect: theoretical background, NOESY.
Synthetic Techniques Applied to the Design and Synthesis of Biologically Active Principles (3CFU)
- "Chemical biology". Definition, history, main descriptors. Differences, strengths and weaknesses with respect to more "classical" genetic approaches for the identification and validation of novel biological targets.
- "Chemical biology". Detailed description of representative examples, including: the identification of a novel target involved with the mitotic process, and useful for the development of oncologic treatments; the elucidation of the role, and the impact of specific kinases on multi-factorial complex diseases such as cancer and Alzheimer's disease; dissection of developmental processes of Danio rerio (zebrafish) embryos.
- Chemical tools (biosensors, probes, affinity reagents, etc.) as a support to target identification and validation.
- Chemical diversity. Numerosity vs. diversity, and implications for the exploration of the so-called "drug-like" space, whose parameters and descriptors (i.e., Lipinski rules, etc.) will be described.
- Chemical diversity. Natural sources (natural products) and artificial sources (organic compounds, combinatorial libraries and parallel arrays, compound collections). How to assemble at best a "diverse" compound collection for high throughput screening, using the available chemical diversity sources.
- Chemical diversity. Detailed description of representative examples, including: assembly and repeated use of a natural products' library for biological target-oriented high throughput screening; synthesis and high throughput screening of a mixture combinatorial library of oligopeptides; synthesis, analytical and biological characterization sintesi of a family of "libraries from libraries" composed by a few sub-sets of "drug-like" organic molecules.
- Rational methods for the design of novel biologically active molecules. "Fragment-based drug discovery"(FBDD): description of the required biophysical platform (X-ray crystallography, NMR spectroscopy, Surface Plasmon Resonance, etc.), suitability of biological target classes, assembly and properties of a suitable fragment collection for FBDD, "ligand efficiency" concept, decoration techniques to increase the potency and/or the selectivity of active fragments from FBDD.
- Rational methods for the design of novel biologically active molecules. Detailed description of meaningful examples, including: "fragment-based discovery" and structural optimization of Bcl-2 inhibitors as novel pro-apoptotic agents for anticancer therapy; "fragment-based discovery" and structural optimization of p38 kinase inhibitors as novel anti-inflammatory agents.