The first part of the course is focused on Chemical Physics Methods for Investigating Molecular Structure (Leonardo Lo Presti)
- Refresh of basic thermodynamic concepts;
- Theory of non-covalent interactions: short-range repulsions, van der Waals and electrostatic interactions, hydrogen bonds, stacking and hydrophobic interactions.
- Molecular mechanics: Force field, modelling of bonding and non-bonding interactions, structure optimization.
- Molecular dynamics. Understanding the rationale beyond molecular dynamics. Ingredients of molecular dynamics (boundary conditions, integrators, structural model, Force Field). Set up of reliable molecular dynamics simulations: problems of solvation, cut-offs, electrostatic interactions and the use of computational barostats and thermostats. Link between molecular dynamics and thermodynamics. Ergodicity.
- Applications. Non-equilibrium (transient) phenomena and related molecular dynamics descriptors. Application of classical simulation methods: structure fluctuations, structure prediction, allostery and molecular docking.
- Introduction to X-ray diffraction. Electromagnetic waves, X-ray scattering, Bragg law, diffraction pattern, hints on cryo-crystallography.
The second part of the course is focused on Rational design of biologically active molecules (Pierfausto Seneci)
- Refresh of protein structure and properties.
- Ligand-protein interactions: enzymes - competitive and non-competitive, allosteric inhibitors; receptors - agonists and antagonists.
- Virtual and tangible drug design: protein / target and small molecule models "in silico"
- Energy minimization, preferred conformations, molecular descriptors.
- Structure-based drug discovery (SBDD): reliable protein models (X-ray, NMR), docking, putative binders' prioritization.
- Ligand-based drug discovery (LBDD): reliable sets of known ligands, pharmacophore generation and validation, similarity searching.
- Fragment-based drug discovery (FBDD): features and advantages of small fragments in drug discovery; X-ray-driven, fast fragment decoration / structural optimization.
- Examples of rational drug design (HSP90 inhibitors - SBDD and LBDD; kinase inhibitors - FBDD).
- Chemical genetics: phenotype screening, chemistry-assisted identification and validation of novel molecular targets in drug discovery.
- Target identification and validation: chemical probes for in vitro experiments (affinity chromatography, SILAC, SPROX, DARTS, etc.).
- Photoaffinity multi-functional probes (azides, diazirines) as covalent markers for proteomics-driven target identification.
- Examples of chemical genetics (zebrafish development screening, uretupamine discovery).
- Examples of chemistry-driven target identification and validation successful studies (bromodomain inhibitors as anti-inflammatory agents, kinesin Eg5 inhibition against cancers).
A revision of the topics covered by the basic chemistry and physics classes included in the bachelor curriculum before attending the course is recommended. No further prerequisites are required other than those specified in the learning manifesto.
Materiale di riferimento
· A. R. Leach. Molecular Modelling. Principles and Applications. Addison Wesley Longman, Essex, England, 1996
· C. Giacovazzo et al., Fundamentals of crystallography, Oxford University Press, 1992
· P. Seneci. Chemical Sciences in Early Drug Discovery: Medicinal Chemistry 2.0. Elsevier, Amsterdam, 2018.
Copies of the slides projected in the classroom as well as other materials will be made available through the course website on the ARIEL platform of the University of Milano (https://lloprestirdscbm.ariel.ctu.unimi.it/v5/home/Default.aspx
). By no means this material replaces the lectures or a textbook. The material is made available only to registered students of the Degree Course in Molecular Biotechnology and Bioinformatics and should not be distributed to others.
Modalità di verifica dell’apprendimento e criteri di valutazione
The final examination consists in a written test (2 hrs long). Students will be prompted to answer to both open questions and questions with a multiple answer choice, in both cases on any topic treated during both the modules. The written exam allows the teachers to evaluate not only the technical competence of the student, but also his/her ability to organize a short dissertation on scientific topics. The final grade will be the joint evaluation of each candidate by the two instructors.
Examples of typical exam questions are available on the Ariel2 website of the course (see below). The instructors are available for arranged meetings, to answer the students' questions at any time before the examination.
Partial evaluations can be arranged in the first semester. These are entirely optional and will consist of two written tests of 2 hrs each, one for each part of the course.
The marks earned by students will be promptly determined, and will be communicated to the students through the ARIEL Webpage of the course.