Rational Design and Structural Characterization of Bioactive Molecules
A.Y. 2024/2025
Learning objectives
This course is intended to provide the student with a theoretical, analytical and applied background in the fields of rational drug design and of target-oriented chemical optimization of bioactive compounds. In particular, modern chemical-physics methods for the investigation of the molecular target-ligand interaction will be discussed in the context of the expanded role of chemistry through the process of the design and optimization of pharmacologically active molecules; and modern, chemistry-directed approaches to assist the identification of novel molecular targets (chemical tools and probes, chemical genetics) will be described.
The course is ideally linked to those dealing with structural biology, bioinformatics, nanotechnologies, protein engineering and molecular enzymology.
The course is ideally linked to those dealing with structural biology, bioinformatics, nanotechnologies, protein engineering and molecular enzymology.
Expected learning outcomes
At the end of the class, the students will be able to:
1. illustrate the basic concepts of equilibrium thermodynamics including internal energy, en-thalpy, entropy, and Gibbs free energy;
2. create suitable mathematical models for an accurate description of the covalent and non-covalent interactions involved in biological phenomena such as protein folding, allostery, and substrate binding;
3. describe the main characteristics of Force Fields employed in computer simulations of bio-molecular systems;
4. illustrate the workflow and main applications of popular computational chemistry tech-niques, i.e. molecular dynamics and Monte Carlo sampling;
5. link the computational study, performed at the microscopic molecular level, of biological phenomena like protein folding to their macroscopic thermodynamical investigation;
6. have understood how computational methods (structure-based, ligand-based and fragment-based drug discovery) support the fast, effective design and optimization of biologically active, small or-ganic molecules; and
7. have learnt about chemical probes for mechanism of action studies in vitro and in vivo (pho-toaffinity ligands, biotin conjugates, etc.); and about their use in target validation studies (affinity chromatography, photoactivation, etc.).
1. illustrate the basic concepts of equilibrium thermodynamics including internal energy, en-thalpy, entropy, and Gibbs free energy;
2. create suitable mathematical models for an accurate description of the covalent and non-covalent interactions involved in biological phenomena such as protein folding, allostery, and substrate binding;
3. describe the main characteristics of Force Fields employed in computer simulations of bio-molecular systems;
4. illustrate the workflow and main applications of popular computational chemistry tech-niques, i.e. molecular dynamics and Monte Carlo sampling;
5. link the computational study, performed at the microscopic molecular level, of biological phenomena like protein folding to their macroscopic thermodynamical investigation;
6. have understood how computational methods (structure-based, ligand-based and fragment-based drug discovery) support the fast, effective design and optimization of biologically active, small or-ganic molecules; and
7. have learnt about chemical probes for mechanism of action studies in vitro and in vivo (pho-toaffinity ligands, biotin conjugates, etc.); and about their use in target validation studies (affinity chromatography, photoactivation, etc.).
Lesson period: First semester
Assessment methods: Esame
Assessment result: voto verbalizzato in trentesimi
Single course
This course cannot be attended as a single course. Please check our list of single courses to find the ones available for enrolment.
Course syllabus and organization
Single session
Responsible
Lesson period
First semester
Course syllabus
The first part of the course (3 CFUs) is focused on Chemical Physics Methods and Theories for Investigating Molecular Structures (Riccardo Conte)
- Refresh of basic thermodynamics concepts;
- Theory of non-covalent interactions: short-range repulsions; van der Waals and electrostatic interactions; hydrogen bonds; stacking and hydrophobic interactions;
- Molecular mechanics: Force fields, modelling of bonding and non-bonding interactions; structure optimization;
- Molecular dynamics: Understanding the rationale behind molecular dynamics. Ingredients of molecular dynamics (boundary conditions, integrators, structural model, Force Fields);
- 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;
- A different approach: The Monte Carlo method;
- A short introduction to the construction of ab initio Potential Energy Surfaces;
- Applications. Non-equilibrium (transient) phenomena and related molecular dynamics descriptors.Application of classical simulation methods: structure fluctuations, structure prediction, allostery and molecular docking.
The second part of the course (3 CFUs) is focused on Rational design of biologically active molecules (Monica Civera):
· Refresh of proteins' structure and properties;
· 3D models of proteins: in silico tools and experimental approaches for the generation of protein structure (AlphaFold, PDB, NMR..);
· One 2-hours training sessions on the use of PDB and AlphaFold;
· 3D models for small molecules: bioactive vs energetically preferred geometries; structural modification, bioisosteric replacements;
· Ligand-protein interactions: definition of the main types of interactions, classification of enzyme and receptors types of ligands: competitive and non-competitive, allosteric inhibitors, agonists and antagonists;
· Target identification and validation
· Structure-based drug discovery (SBDD) approaches: docking calculations and virtual screening;
· Ligand-based drug discovery (LBDD) approaches: pharmacophore and QSAR models;
· 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);
- Refresh of basic thermodynamics concepts;
- Theory of non-covalent interactions: short-range repulsions; van der Waals and electrostatic interactions; hydrogen bonds; stacking and hydrophobic interactions;
- Molecular mechanics: Force fields, modelling of bonding and non-bonding interactions; structure optimization;
- Molecular dynamics: Understanding the rationale behind molecular dynamics. Ingredients of molecular dynamics (boundary conditions, integrators, structural model, Force Fields);
- 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;
- A different approach: The Monte Carlo method;
- A short introduction to the construction of ab initio Potential Energy Surfaces;
- Applications. Non-equilibrium (transient) phenomena and related molecular dynamics descriptors.Application of classical simulation methods: structure fluctuations, structure prediction, allostery and molecular docking.
The second part of the course (3 CFUs) is focused on Rational design of biologically active molecules (Monica Civera):
· Refresh of proteins' structure and properties;
· 3D models of proteins: in silico tools and experimental approaches for the generation of protein structure (AlphaFold, PDB, NMR..);
· One 2-hours training sessions on the use of PDB and AlphaFold;
· 3D models for small molecules: bioactive vs energetically preferred geometries; structural modification, bioisosteric replacements;
· Ligand-protein interactions: definition of the main types of interactions, classification of enzyme and receptors types of ligands: competitive and non-competitive, allosteric inhibitors, agonists and antagonists;
· Target identification and validation
· Structure-based drug discovery (SBDD) approaches: docking calculations and virtual screening;
· Ligand-based drug discovery (LBDD) approaches: pharmacophore and QSAR models;
· 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);
Prerequisites for admission
Knowledge 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.
Teaching methods
Classroom lectures supported by projected material and provided lecture material - pdf files and, when available, mp4 recordings on the Ariel Website. The attendance is highly recommended.
Teaching Resources
· A. R. Leach. Molecular Modelling. Principles and Applications. Addison Wesley Longman, Essex, England, 1996
· P. Seneci. Chemical Sciences in Early Drug Discovery: Medicinal Chemistry 2.0. Elsevier, Amsterdam, 2018.
· P. Seneci. Chemical Sciences in Early Drug Discovery: Medicinal Chemistry 2.0. Elsevier, Amsterdam, 2018.
Assessment methods and Criteria
The final examination consists in a written test (2 hrs long, 1 hour each for the two modules). 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.
CHIM/02 - PHYSICAL CHEMISTRY - University credits: 3
CHIM/06 - ORGANIC CHEMISTRY - University credits: 3
CHIM/06 - ORGANIC CHEMISTRY - University credits: 3
Lectures: 48 hours
Professors:
Civera Monica, Conte Riccardo
Professor(s)
Reception:
Chemistry Dep., building 5B, 3rd floor, room 3021
Reception:
To be agreed via email. Please send an email to [email protected]
Department of Chemistry, First Floor, Sector A, Room 131