73219 - Functional Design of Molecules

Course Unit Page

Academic Year 2018/2019

Learning outcomes

At the end of the course the student acquires the basic knowledge on modern computer methodologies and computational procedures applied to chemistry and in particular to pharmaceutical chemistry which find very important applications in the field of drug design and optimization of new drugs. The student also knows the phases of the drug design process and knows how to use computational techniques suitable to solve specific problems; the student can also quantify the molecule-target interactions and predict, starting from the molecular structure, the physical properties, the activity and the bio- and eco-distribution of the molecule.

Course contents

1) Interactions between Molecules, Thermodynamics in Supramolecular Interactions, Van der Waals Forces, Hydrophobic Effect, Hydrogen Bonding, Non-classical Hydrogen Bonding, Ionic Interactions ("salt bridges"), Halogen bonds, Dipolar and Multipolar Interactions, pi-Stacking, Cation / Anion-pi.

2) Chemoinformatics

Principles of Chemoinformatics - Molecular Representation, 1D, 2D and 3D Molecular Classification, - Database Searching - Structural Keys - Molecular Similarity and Diversity - Substructure

3) Quantitative Structure Activity/Property Relationship, QSA(P)R, Molecular Descriptors - Classification and Analysis of Molecular Descriptors - 1D, 2D and 3D Descriptors, Quantitative Relationship Structure-Activity / Properties - Predictors of pKa, Lipophilia and Solubility

4) Development and Optimization of a Drug, Stages of Drug Development - Pre-Clinical Trials, Clinical Phase: Costs and Problems - Computational Methodologies Employed During the Steps Drug Development Process: Target Identification and Validation - Identification of a Lead Compound - Optimization of the Pharmalogical Activity - Optimization of Chemical-Physical Properties of the Molecule - ADMET Optimization

5) "Ligand Based Drug Design"

Fields of Application, Pharmacopoeic Models, Definition of Pharmacophore, Pharmacophore Scoring, Pseudoreceptorial Models, QSAR, Hansch Equation, Free-Wilson Equation, Craig-Plots, Comfa, Grid

6) "Structure Based Drug Design"

Target Identification, Three-dimensional Structure of Proteins, Active Site of a Protein, Inhibition and Allosteric Effect, Protein Data Bank, Bioinformatics, Protein Structure Prediction, Protein-Molecule Interaction, Rigid Docking, Scoring Functions, Conformational Analysis, Flexible Docking , Protein-Protein Docking, De-novo Derug Design, Molecular Mechanics, LIE and MM-PBSA, Molecular Dynamics, Advanced MD Sampling Techniques (Metadynamics, Umbrella Sampling, FEP, Steered MD).

7) Virtual screening

Molecular Database, Problems Related to Molecular Database (Tautomerism, Protonation State), Inverse Docking, Annotated Database

8) Biodistribution, Models of Ecodistribution

Compartmental Models, Dose-Response Evaluation, Threshold, Pharmacokinetic Models, ADMET, Life Cycle Modeling, Environmental Exposure Models.

9) Design of Catalysts, Design of Supramolecular Hosts, Self-Assembly, Principles of Crystal Engineering


The basic reading material will be the teachers' slides and notes; this material will be available on-line.

For further information, the following bibliography is suggested:

• A. R. Leach, “Molecular Modelling: Principles and Applications” , Pearson Education EMA

Teaching methods

The Course consists of lectures accompanied by "case studies" with the aim of showing the practical application, in the real world of research and industry, of the methodologies presented in class.

Assessment methods

The assessment takes place only through the final exam, which ensures the acquisition of knowledge and skills expected by conducting an oral exam. This consists in the critical analysis of a functional design problem of a molecule. The student must define the tools to be used in the design, contextualize the choice within the global process and show the theoretical mastery of the techniques used. The duration of the oral exam is on average 30 minutes.

Teaching tools

PC, video projector

Office hours

See the website of Matteo Calvaresi