This exam is present in the following Optional Group

Objectives

General expected learning outcomes
The course of Medicinal Chemistry and Toxicology 3 aims to start the student, in a multidisciplinary study, to approach a very recent and current science, which has made great strides in the last twenty years in various areas of research: epigenetics. Short subjects of genetics, biology, biochemistry, pharmacology and toxicology will be treated as essential notions to the study, even if the main course will be the chemical-pharmaceutical/medicinal aspect of epigenetics, that is the validation of the various epigenetic targets for the various pathologies, first of all the cancer, and rational design and the latest methods of identifying interfering compounds or modulators of such targets. Particular emphasis will be given to drugs approved for clinical use and those in advanced stages of clinical study. In a parallel task rational drug design techniques, focusing on ligand-based approaches such as QSAR a 3-D QSAR will be illustrated both in theory and in practical.

Specific expected learning outcomes
1. Knowledge and understanding
The student will know all the chemical-pharmaceutical aspects of the epigenetic ligands with particular regard to those approved or in an advanced phase of clinical study. Fundamentals will be the catalytic mechanisms and the biological implications of the targets involved in the development of pathologies. In the section of rational drug design the student will be introduced to computational techniques to better understand ligand/target interactions.

2. Applying knowledge and understanding
At the end of the course the student will recognize, when possible, the known pharmacophoric models useful for the design of new ligands for those particular epigenetic targets. He will know which are the most relevant structure-activity relationships on these compounds, and which are the points of the drug that can be chemically modified and which ones cannot be altered otherwise the loss of biological activity. He will know the effects of these compounds on the altered signal pathways leading to pathologies, with particular reference to the apoptotic, necrotic and autophagic pathways. He will know the most important and widespread therapeutic problems and the therapeutic solutions available within an epigenetic therapy. Computational techniques will enable the student to quantify the relationships between bioactivity and chemical modifications.

3. Making judgements
The lessons will be all interactive, in which the teacher will ask the students continuous questions to stimulate them and develop their critical sense. These questions will also serve to evaluate and solicit students to make connections with everything studied so far, avoiding to consider the study of the subject a study in itself but integrating the pharmaceutical chemistry in light of the knowledge already acquired, both chemical (organic, biochemical chemistry) than biological (pathology, pharmacology, toxicology).

4. Communication skills
The evaluation of the student's study will be carried out only with an oral exam, which will focus on the topics of the program, testing the student's communication skills with respect to what he has learned. Much appreciated in recent years by students is the powerpoint mode, in which the teacher assigns them a scientific article in epigenetics and they must prepare and describe in a ppt presentation the assumptions, rational and results of the same study, even with a critical judgment on the work of authors and on the construction / management of work.

5. Learning skills
The student will find the deepening of what he heard in class on recommended scientific reviews.

Channels

NESSUNA CANALIZZAZIONE

ANTONELLO MAI ANTONELLO MAI   Teacher profile

Programme

Program
Introduction on epigenetics
DNA methyltransferase: biology and inhibitors. Catalytic mechanism. Nucleoside and non-nucleoside inhibitors.
Cross-talk between epigenetic modifications.
Histone deacetylases: biology and inhibitors. Catalytic mechanism. Pharmacological model for inhibitor design. Activity on tumor cells.
Sirtuins: biology and modulators. Catalytic mechanism. Therapeutic potentials.
Histone acetyltransferases: biology and modulators.
Histone methyltransferases: biology and inhibitors. Methyltransferases for arginine (PRMTs) and lysine (HKMTs): specific inhibitors. EZH2 inhibitors.
Histone demethylase: biology and inhibitors. LSD1 inhibitors. JMJ inhibitors.
Acetyl-readers and methyl-readers.
Chemical-pharmaceutical applications of epigenetic modulators in cancer.
Small molecules as modulators of epigenetic targets: use in non-cancer pathologies.
Medicinal chemistry quantitative approaches: the Hansh QSAR and linear models to build quantitative structure-activity relationship (MLR and PLS). Evaluation and validation of models: r2, q2 and SDEP.
QSAR evolution: the 3-D QSAR. How to build a model and give its interpretation.

Adopted texts

Dany Pechalrieu, Chantal Etievant, Paola B. Arimondo. DNA methyltransferase inhibitors in cancer: From pharmacology to translational studies. Biochemical Pharmacology 129 (2017) 1–13.
Cheryl H. Arrowsmith, Chas Bountra, Paul V. Fish, Kevin Lee, Matthieu Schapira. Epigenetic protein families: a new frontier for drug discovery. Nature Reviews Drug Discovery 11 (2012) 384-400.
Aidan Finley, Robert A. Copeland. Small Molecule Control of Chromatin Remodeling. Chemistry & Biology 21 (2014) 1196-1210.
Pasano Bojang Jr., Kenneth S. Ramos. The promise and failures of epigenetic therapies for cancer treatment. Cancer Treatment Reviews 40 (2014) 153–169.
Robert A Copeland, Edward J Olhava and Margaret Porter Scott. Targeting epigenetic enzymes for drug discovery. Current Opinion in Chemical Biology 14 (2010) 505–510.
Roy M. Pollock, Victoria M. Richon. Epigenetic approaches to cancer therapy. Drug Discovery Today: Therapeutic Strategies 6 (2009) 71-79.
Stephen B. Baylin, Peter A. Jones. A decade of exploring the cancer epigenome — biological and translational implications. Nature Reviews Cancer 11 (2011) 726-734.
Francesco Fiorentino, Antonello Mai, Dante Rotili. Lysine acetyltransferase inhibitors: structure-activity relationships and potential therapeutic implications. Future Med Chem. (2018) Apr 20. doi: 10.4155/fmc-2017-0244.
V Carafa, D Rotili, M Forgione, F Cuomo, E Serretiello, GS Hailu, E Jarho, M Lahtela-Kakkonen, A Mai, L Altucci. Sirtuin functions and modulation: from chemistry to the clinic. Clin Epigenetics 8 (2016) 61.
C Zwergel, S Valente, C Jacob, A Mai. Emerging approaches for histone deacetylase inhibitor drug discovery. Expert Opin Drug Discov 10 (2015) 599-613.

Exam reservation date start Exam reservation date end Exam date
15/12/2020 16/01/2021 20/01/2021
20/01/2021 14/02/2021 18/02/2021
01/04/2021 12/05/2021 17/05/2021
20/05/2021 17/06/2021 21/06/2021
22/06/2021 18/07/2021 22/07/2021
20/08/2021 16/09/2021 20/09/2021
10/10/2021 04/11/2021 08/11/2021

RINO RAGNO RINO RAGNO   Teacher profile

Programme

Program (see also in https://elearning.uniroma1.it/course/view.php?id=912)
============================================================================
Prof. Mai:
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Introduction on epigenetics
DNA methyltransferase: biology and inhibitors. Catalytic mechanism. Nucleoside and non-nucleoside inhibitors.
Cross-talk between epigenetic modifications.
Histone deacetylases: biology and inhibitors. Catalytic mechanism. Pharmacological model for inhibitor design. Activity on tumor cells.
Sirtuins: biology and modulators. Catalytic mechanism. Therapeutic potentials.
Histone acetyltransferases: biology and modulators.
Histone methyltransferases: biology and inhibitors. Methyltransferases for arginine (PRMTs) and lysine (HKMTs): specific inhibitors. EZH2 inhibitors.
Histone demethylase: biology and inhibitors. LSD1 inhibitors. JMJ inhibitors.
Acetyl-readers and methyl-readers.
Chemical-pharmaceutical applications of epigenetic modulators in cancer.
Small molecules as modulators of epigenetic targets: use in non-cancer pathologies.
============================================================================
Prof. Ragno:
============================================================================
Methods to write molecule at the computer with practical sections
Analysis of ligand/receptor interactions by means of molecular graphics software
Medicinal chemistry quatitative approaches: the Hansch QSAR and linear models to build quantitative structure-activity relationships (MLR and PLS). Evaluation and validation of models: r^2, q^2 and SDEP.
QSAR evolution: the 3-D QSAR. How to build a model and give its interpretation
Introduction to the Structure-Based methods focusing on molecular docking of small molecules into proteic macromolecules
Practical sections in molecular docking with Autodock Vina

Adopted texts

Chimica farmaceutica di Patrick L. Graham. Part D
https://elearning.uniroma1.it/course/view.php?id=912

Prerequisites

Indispensable: for the comprehension of the lessons of Medicinal Chemistry and Toxicology 3 the notions of math, organic chemistry, biochemistry, medicinal chemistry and toxicology 1 and 2 are indispensable.

Study modes

The teaching of Medicinal Chemistry and Toxicology 3 consists of lectures with students. The lessons are all interactive, so the teacher stimulates the students with questions to which, by virtue of the courses already Folflowed, they can give an answer. This allows the teacher to make evident the links between the current course and some previous courses, whose notions play a key role in understanding what is proposed in class. Continuous references to concepts of previous courses must make the student accustomed to not studying the proposed subject as something closed, aimed at passing the final exam, but wants to highlight a multidisciplinary study, to which the student is educated, and that is absolutely required for a student of the 4th or 5th year, now almost at the end of his training. The student will find on the e-learning platform the slides and the teaching material (exam program, recommended bibliography) useful for the preparation of the exam. It is understood that the slides are a guide to the exam topics, but they can never completely substitute for the lectures given by the teacher and the recommended bibliography. The lections will be on live e can be attended either in room (with the necessary security measures) or online with the timetable published in https://corsidilaurea.uniroma1.it/cdlcontroller-orari-cdl/2020/29892 For the computational medicinal chemistry lectures the online followers will be able to attend the lecture through the Google Meet virtual room meet.google.com/kdp-pcye-yek

Exam modes

The course evaluation methods are characterized an oral exam call set for almost every month of the year, excluding the month of August. The oral examination, based on the choices of the students, can be based on the program of the course, or it can be based on a ppt presentation that students will prepare starting from a scientific article on epigenetic modulators taken from scientific journals of medicinal chemistry with high impact factor, and chosen by the teacher. In this case the students will have to frame the target based on the references shown in the bibliography of the article, then they will expose the rationale of the work and finally data, results and conclusions. At the end of the exhibition students will be asked for a critical opinion on the analyzed work. The oral exam lasts on average 30/35 minutes per student. The objective of the test is to certify the student's knowledge about targets and epigenetic compounds, and the ability to read, understand and exhibit scientific work for those who have chosen the article mode. The topics presented should be treated with a language appropriate to a drug expert. The elements taken into consideration for the purposes of evaluation are: knowledge of the subject, the use of appropriate language, active participation during the lectures, the ability of reasoning demonstrated in the examination interview, the ability to study independently on the articles indicated / assigned. Sufficient knowledge of the topics covered is required for passing the exam with minimum grades. To achieve a score of 30/30 cum laude, the student must demonstrate that he has acquired excellent knowledge of all the topics covered during the course, being able to link them in a logical and consistent way. In the case of the choice of the "article" option, the student must be able not only to understand and expose the assigned scientific work in an excellent manner, but also to respond to the insights that the teacher will ask at the end of the presentation.
For the drug design part, during the course will be given assignements to evaluate the student active participation, this will be taken into account for the final mark. During the final presentation the student should prove to have acquired the thought techniques by having applied them to the assigned article molecules or through a practical demonstration.

Course sheet
  • Academic year: 2020/2021
  • Curriculum: Curriculum unico
  • Year: Fourth year
  • Semester: First semester
  • SSD: CHIM/08
  • CFU: 8
Activities
  • Attività formative affini ed integrative
  • Ambito disciplinare: Attività formative affini o integrative
  • Lecture (Hours): 64
  • CFU: 8
  • SSD: CHIM/08