Rational design and structural characterization of bioactive molecules

A.Y. 2018/2019
Overall hours
Learning objectives
This course is intended to provide the student with a theoretical, analytical and applied background in the fields of drug design and of target-oriented chemical optimization of bioactive compounds
Expected learning outcomes
Course syllabus and organization

Single session

Course syllabus
Part 1a: This part aims to provide an overview of modern chemical-physics methods for the investigation of the molecular structure.
Part 1b: This part aims at introducing basics principles of NMR spectroscopy, with emphasis on its application on organic compounds
Part 2: This part aims at illustrating the expanded role of chemistry in all the stages spanning through the initial concept idea, the rational design, the synthesis and the structural optimization of a pharmacologically active molecule.

Part 1a (Leonardo Lo Presti, 3 university educational credits)
Chemical Physics Methods for Investigating Molecular Structure (3 university educational credits)
- Non-covalent interactions: 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. Introduction to molecular dynamics and stochastic methods. Molecular docking. Worked cases applied to simple systems of biological interest (e.g. membranes, drug:receptor interactions).
- Introduction to crystallography. Point groups, space groups. Generation of X-rays. Synchrotron light sources. Bragg Law. Application to problems of pharmaceutical interest.

Part 1b (Donatella Potenza, 1 university educational credit)
NMR spectroscopy
Nuclear Magnetic Resonance Spectroscopy (NMR). Basic principles.
Chemical shift, coupling constant and Overhauser effect (NOE) in 1H- and 13C-NMR experiments. NMR applied to structure elucidation of bioactive molecules. NMR spectroscopy in biochemistry: STD and Tr-NOESY experiments.

Part 2 (Pierfausto Seneci, 2 university educational credits)
Synthetic Techniques Applied to the Design and Synthesis of Biologically Active Principles
- "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.

Lecture notes. C. Giacovazzo et al., Fundamentals of crystallography, Oxford University Press, 1992. H. Friebolin "Basic One- and Two-dimensional NMR spectroscopy" Ed. VCH.

No further prerequisites are required other than those specified in the learning manifesto.
The final examination will consist of two written tests, one for each part (1, 2) of the course. Ongoing evaluations could be also arranged. The final grade will be determined by the CFU-weighted average of the two examinations.

Very basic knowledge of kinematic physics, thermodynamics and trigonometry is recommended.

Classroom lessons


The Ariel platform (http://ariel.unimi.it/User/Default.aspx) hosts the pertinent teaching material for this course.
CHIM/02 - PHYSICAL CHEMISTRY - University credits: 0
CHIM/06 - ORGANIC CHEMISTRY - University credits: 0
Lectures: 48 hours
To be arranged by e-mail
Dr. Lo Presti Office R21S, Dept. of Chemistry, Ground Floor, South Section