Rational drug design to treat a variety of diseases plaguing humans is a dream, which is fast becoming a practically achievable goal of computer-aided drug discovery research. This course will expose the student to methods and application of computational drug design providing a historical overview followed by an in-depth introduction to present-day methods. The history of drug research can be divided into several phases characterized by: empirical methods, targeted isolation of active compounds from plants, systematic search for new synthetic materials with desired biological effects and the introduction of animal models as surrogates for patients, the use of in vitro test systems as a replacement for animal experiments, the introduction of molecular-level methods such as protein crystallography, molecular modeling. Today, quantitative structure–activity relationships are found for targeted structure-based and computer-aided design of drugs. Discoveries of new targets and the validation of their therapeutic value is achieved through genomic, transcriptomic, metabolomic and proteomic analysis, knock-in and knockout animal models, and gene silencing with siRNA. Main focus will be placed on both ligand-based and structure-based computer-aided design of an active substance, which is validated by in vitro and in vivo tests to determine the activity of new investigational compounds. The course can be taken in both the first and second year of degree.

The course offers a description of the state of the art of computer-aided drug design and biomedical modelling within both academic research and pharmaceutical/biotech industry applications starting from a historical perspective providing a solid theoretical basis of the presented computational approaches. Practical cases will be the objective of specific hands-on tutorials. The student will gain competence in specific computational techniques at the level of molecular target modeling, ligand-protein interactions and pharmacokinetic simulations. To better understand the practical use of these methods, case studies will discuss examples of drug development from oncology, virology and immunology At the end of the course the student will be able to: • Understand molecular modeling approaches and force fields applied to drug-target systems. • Develop Homology models of Proteins • Perform bioinformatics and chemo-informatic database mining • Employ Ligand Based drug screening/discovery/design algorithms • Employ Structure Based drug screening/discovery/design algorithms with particular focus on drug-target docking simulations and fast binding affinity predictions • Understand the basis of pharmacokinetic modeling, use software for ADMET prediction, Develop pharmacophore models, perform a QSAR determination. This course will help students to develop their independent thinking through self-assessment tests. The ability to learn is stimulated by a training program that alternates, in an organized schedule, methodological principles, application examples, and exercises. The course will help to improve both written and oral communication skills through classroom exercises, group and individual tutorials and through the development of a short applied project focused on drug design. The applied project will encourage the students to undertake surveys on websites, to view the scientific literature and to become aware of the applied research areas related to the course.

Good knowledge of the basics of engineering with particular attention to physics, mathematics, chemistry, biology, mechanics, materials science. Whereas not strictly required, the courses “From Molecules to Organs” and “Modelli Biomeccanici Multiscala” are suggested to provide a complete view of the faced topics. The lecturer may consider filling specific background gaps by giving ad hoc lectures.

• Historical overview of drug discovery • Introduction to modern drug design and development • Bioinformatic, chemi-informatic and pharmacological Databases • Drug design and discovery. • Protein Homology Modelling • Ligand/receptor docking for affinity calculation. Drug binding kinetics • Virtual Screening • Pharmacophore development • QSAR methodology • Pharmacokinetics and ADMET prediction • Basis of Molecular Mechanics and QM/MM for precise investigation of drug-protein binding interface • Basis of Classical Molecular Dynamics and Enhanced Sampling for investigating drug effects on protein conformation • NanoParticle Design for drug delivery

32 lectures, 28 lab sessions

Lectures, classroom exercises and hands on practice sessions in the computational lab.

The teacher will provide all the course material (slides and lecture notes). Suggested textbooks: • D.C. Young, Computational Chemistry, John Wiley &Sons, 2001 • Leach, A.R., 2001. Molecular modelling : principles and applications. Prentice Hall. • R.D. Hoffmann, A. Gohier and P. Pospisil (eds.) Data Mining in Drug Discovery, Wiley-VCH, 2014 • G. Klebe (ed.), Drug Design: Methodology, Concepts and Mode-of-Action, Springer, 2013

Modalità di esame: Prova scritta (in aula); Prova orale facoltativa; Progetto di gruppo;

Exam: Written test; Optional oral exam; Group project;

... A plan for student evaluation might be. Written/Oral Exam (depending on the student number) + a team project which will be mandatory A written exam will be of 2-hour duration and the student will only be allowed to use a calculator during the exam. The project will be based on an applied problem on drug design to be solved by a student team. The project might consider: homology models, ligand based modelling, drug-protein docking, pharmacophore modelling. The grades will range from 0 to 33. Those students who score at or above 31 will be given a designation: "laude".

Gli studenti e le studentesse con disabilità o con Disturbi Specifici di Apprendimento (DSA), oltre alla segnalazione tramite procedura informatizzata, sono invitati a comunicare anche direttamente al/la docente titolare dell'insegnamento, con un preavviso non inferiore ad una settimana dall'avvio della sessione d'esame, gli strumenti compensativi concordati con l'Unità Special Needs, al fine di permettere al/la docente la declinazione più idonea in riferimento alla specifica tipologia di esame.