Ateneo - UPO

Module A
Medicinal Chemistry definition.
Pharmaceutical Phase
Routes of administration.
Pharmacokinetic Phase
Absorption.
Distribution.
Elimination. Metabolism. Excretion.
Pharmacodynamic Phase
Intermolecular interactions.
Role of stereochemistry in the interaction with the binding site.
Receptors as drug targets. Enzymes as drug targets. Miscellaneous drug targets.
Hit compound and lead compound. Finding a lead. How to recognize drug-like molecules.
Drug optimization.
The optimization of target interactions. The optimization of the access to the target.
Drug development.
Preclinical and clinical trials.
Exercises.
Module B
1) Antiprotozal drugs
2) Antibacterial drugs
3) Antiviral drugs
4) Antitumoral drugs
5) Antifungal drugs
Exercises.

G. Costantino, G. Sbardella, Chimica Farmaceutica, EdiSES
A. Gasco, F. Gualtieri, C. Melchiorre Chimica Farmaceutica Casa Editrice Ambrosiana;
W. Foye, Principi di Chimica Farmaceutica, Piccin;
Medicinal Chemistry: The Modern Drug Discovery Process, E. Stevens

The aim of module A is to introduce the student to the main principles of medicinal chemistry, while module B aims at describing the main drugs used in chemotherapy and integrates with the next course in Medicinal Chemistry 2 for the discussion of the other classes of drugs.
The specific objectives of the course, according to the Dublino descriptors, are the following:
1. Knowledge and understanding. At the end of the course the student will know and understand the basic concepts of medicinal chemistry, in particular the route followed by the drug in the organism, from its administration to its excretion (pharmaceutical, pharmacokinetic, pharmacodynamic phases). Moreover, the itinerary of the drug in the pharmaceutical industry, from drug discovery to drug development through drug design, will be addressed. The student will also know and understand the main drugs used in chemotherapy.
2. The student will apply the acquired knowledge and understanding in the recognition of the chemical structures, in the discussion of the chemical and chemico-physical properties, of the mechanism of action, of the structure-activity relationship, of the metabolic fate and of the plausible routes for the synthesis of drugs.
3. The student will acquire the ability to identify and use data to formulate responses to well-defined concrete and abstract problems regarding the structure-activity relationship, the metabolism, the related toxicity, the synthesis, the drug-drug interaction for specific cases of drugs. Moreover, the student will be provided with all the tools necessary for the critical analysis of texts and papers in the medicinal chemistry literature.
4. The student will learn to communicate about his/her understanding, to describe, even in an original way, a topic described during lessons, to adequately answer to questions, critiques and suggestions.
5. The student will have the learning skills to handle in a dinamic way his/her knowledge in medicinal chemistry with some autonomy.

In order to give the exam in Medicinal Chemistry I it is necessary that the student has passed the exam in Organic Chemistry II.
Good knowledge in general biology, biochemistry, general pharmacology and human physiology is strongly recomended.

The course is given with the support of slides, which are given to the students at the beginning of the lessons.
General and specific topics will be introduced, basic concepts will be provided for the understanding of each issue, and discussions with the students will be held. It will be explained how to acquire the competences needed to predict the chemical and physico-chemical properties of drugs starting from their structures, to identify the structural elements necessary for their mechanism of action and to recognize alert groups that can lead to toxicological problems. At the end of each module practical exercises will be solved in order to prepare the students to the exam.

Students with physical disabilities, Learning Disabilities or Special Education Needs can request specific services and tools via the Staff Sviluppo e Coordinamento Carriere e Servizi alle Studentesse e agli Studenti, consulting the University webpage: https://www.uniupo.it/en/services/services-students-physical-or-learning-disabilities

Students with disabilities, learning disabilities or special education needs, once they have contacted the University Staff, can refer to the tutor in charge of the course to define the examination modalities, concerning academic aspects.

Module A
The exam consists in a written test displaying 15 questions. 10 questions are general and cover the program of the course. 5 questions are exercises regarding a drug molecule whose structure is given by the professor. These exercises consist in the identification of acid and basic centers, stereogenic centers, intermolecular interactions, possible metabolism reactions, etc.
In order to get a sufficient evaluation, the student needs to answer correctly to 9 questions over the 15 given.
Module B
The exam consists in a written test displaying: 1) two questions (10 points each) where a structure of a drug is given and ten brief questions are asked (1 point each); 2) one question (10 points) in which two structures are given and the student must indicate the corresponding INN, the mechanism of action and the therapeutic indication; 3) one question (2 points) in which the student must indicate the structure of a drug when the INN is given. The exam is considered sufficient when a mark of at least 18/30 is reached.
The student has to demonstrate to be able to recognize a chemotherapy drug from its structure, to identify the functional groups, the acid, basic and stereogenic centers, the plausible reactions of metabolism, the routes for its preparation, etc.
Through these tests, it will be verified that the student has achieved the objectives of knowledge and understanding of the contents of the course, the ability to communicate these concepts in a clear and correct manner and the competence to apply the acquired knowledge and skills to specific concerns regarding the medicinal chemistry of the different classes of drugs.
For both the exams, in the case that the student gets a mark less than 12, he or she cannot take the exam in the following date of the exam.

Module A
Medicinal Chemistry definition.
Pharmaceutical Phase
Routes of administration.
Pharmacokinetic Phase
Absorption. Mechanisms of absorption. Passive diffusion. Partition coefficient. Fick law. Henderson-Hasselbach equation. Ion-pair absorption. Carrier mediated transport. Vescicolar transport. Convective trasport. The absorption in the oral administration: first-pass metabolism.
Distribution. Plasma protein binding. Accumulation. Blood-brain barrier. Placental barrier.
Elimination. Renal excretion. Phase I and phase II metabolism. Soft e hard drugs.
Pharmacokinetic concepts. Plasma concentration-time curve. Clearance. Half-life. Bioavailability. Apparent volume of distribution.
Factors that influence pharmacokinetics.
Pharmacodynamic Phase
Intermolecular interactions. Covalent bond. Ionic bond. Dipole-dipole interaction. Ion-dipole interaction. Hydrogen bond. Halogen bond. Charge transfer. Van der Waals interactions. Hydrophobic interactions. Pi greco-pi greco interactions.
Role of steoreochemistry in the interaction with the binding site. Three point contact model. Pfeiffer rule. Eutomer, distomer, eudismic ratio. Chiral switch. Methods for the chiral switch.
Receptors as drug targets: theories, strategies to design agonists, antagonists, allosteric modulators, inverse agonists.
Enzymes as drug targets: competitive reversible, non competitive reversible, irreversible inhibitors, transition-state analogues, suicide substrates.
Miscellaneous drug targets: transport proteins as drug targets, structural proteins as drug targets, protein-protein interactions, lipids as drug targets.
Hit compound and lead compound. Choosing a disease, a drug target, a bioassay. High-throughput screening, NMR screening, virtual screening. Parallel and combinatorial synthesis.
Finding a lead: natural products, serendipity, natural ligand modifications, me-too drugs, SOSA approach, screening, de novo drug design, fragment-based drug design.
How to recognize drug-like molecules. Lipinski and Veber rules.
Drug design
The optimization of target interactions: structure-activity relationships, isosteres and bioisosteres, classic and non classic bioisosteres, pharmacophore identification, drug design strategies (extension, chain extension/contraction, homology, vinilogy, benzology, ring expansion/contraction, ring variations, ring fusion, structure simplification, structure rigidification, conformational blockers, twin drugs and hybrids).
The optimization of the access to the target: how to optimize the hydrophobic and hydrophilic properties, how to improve the chemical and the metabolic stability, prodrugs, mutue prodrugs.
Drug development
Preclinical and clinical trials.
Exercises on specific molecules of drugs.
Module B
Antimalarials.
Antibacterial agents: antimicobacterial, sulfonamides, dihydrofolate reductase inhibitor, quinolones, oxazolidinones, nitroderivatives, β-Lactam antibiotics, penicillins, cephalosporins, monobactams, carbapenemes, aminoglycosides, tetracyclines, macrolides, other drugs.
The classification and biochemistry of viruses. Nucleoside antimetabolites, agent for the treatment of HIV infection and hepatatis C.
Anticancer drugs: classification, alkylating agents, antimetabolites, protein kinase inhibitors, miscellaneous compound.
Antifungal: most important agents.
Exercises.

The student at the end of the course will know the basic principles of medicinal chemistry, both in pharmacodinamics and pharmacokinetics. These aspects will be fundamental in order to follow the module B and the Medicinal Chemistry II course. Furthermore, he/she will be able to apply these principles to a specific bioactive molecule and to evaluate its chemical ,metabolic and drug-likeness properties. The student will also know the role of medicinal chemistry in drug discovery and in drug design and the strategies that can be used in order to improve the pharmacodinamic and pharmacokinetic properties of a bioactive molecule.