90823 - Biomolecular Simulations for Drug Design

Learning outcomes

At the end of the course, the student knows the theoretical and practical aspects related to molecular simulations of pharmaceutically relevant biological systems. In particular, the student knows the basics of several computational methods (including docking and Molecular Dynamics), and how to integrate them for designing or selecting bioactive compounds. Finally, the student is able to plan and setup virtual experiments and run calculations with widespread open-source software for biomolecular simulations.

Course contents

Module 1 (3 CFU: 24 hours, frontal lectures)

• Introduction and basic concepts.
  The drug action process: pharmaceutical phase, pharmacokinetics, pharmacodynamics
  Molecular targets of drug action: definition and examples; thermodynamic representation of drug-target interaction. Drug-target interactions: covalent bond and non-covalent interactions, enthalpic and entropic contributions.

• The paradigm of drug discovery.
  The "magic bullet"; examples: penicillins, steroid hormone derivatives, kinase inhibitors.
  Polypharmacology and multi-target drugs.
  Targeting signaling pathways and systems.
  

• In silico drug design strategies.
  Structure-based approaches: Virtual Screening; FBDD (Fragment-Based Drug Design).
  Ligand-based approaches: pharmacophores and database searching; QSAR and chemoinformatics.
  Network-based approaches.

• Presentation of case studies.

Module 2 (1 CFU: 8 hours, frontal lectures; 2 CFU: 30 hours, laboratory)

• Molecular modeling.
  Potential energy functions.
  Minimization algorithms.
  Conformational analysis: systematic search and genetic algorithms.
  Fundamental principles of Monte Carlo simulations.
  Practical aspects of molecular docking.
  

• Molecular Dynamics Simulations.
  Fundamental principles of Molecular Dynamics simulations.
  Calculation of experimentally relevant observables for pharmaceutical interest through Molecular Dynamics simulations.
  

• Hands-on exercises with dedicated software.
  Drawing and construction of small molecules.
  Protein crystal structures for structure-based drug design (Protein Data Bank).
  Setting up and performing molecular docking calculations.
  Setting up and performing Molecular Dynamics simulations.

Readings/Bibliography

Reading material provided by the teachers during the lectures.

A.R. Leach, Molecular Modelling: Principles and Applications, Person Education Limited, 2nd edition, 2001.

Teaching methods

Frontal lectures and training exercises on the computer with the support of tutors.

In consideration of the type of activity and the teaching methods adopted, the attendance of this training activity requires the prior attendance of all students to the training Modules 1 and 2 on safety in the study places, in e-learning mode.

Assessment methods

Students will be required to present and discuss orally a written short summary (3-5 pages) of a research paper retrieved from the literature reporting a work dealing with an argument inherent to the course contents (computational design/identification of bioactive compounds).
In addition, further questions inherent to the whole course contents will be asked (including the laboratory).

Teaching tools

Electronic slides, scientific papers, and other teaching materials available through the Virtuale platform.

Office hours

See the website of Matteo Masetti