Ateneo - UPO

The course will deal with the processes inherent the discovery, optimization and validation of molecules with biological activity (Lead discovery , lead optimization, QSAR, molecular modeling, ADMET).

Chimica farmaceutica (Seconda edizione), Alberto Gasco, Fulvio Gualtieri, Carlo Melchiorre. Febbraio 2020. ISBN: 978-8808420268 Principi di chimica farmaceutica (Settima edizione). William O. Foye, Thomas L. Lemke, S. William Zito, Victoria F. Roche, et al. Giugno 2021. ISBN: 978-8829931538 An Introduction to Medicinal Chemistry (Seventh Edition), Graham Patrick. March 2023. ISBN: 978-0198866664 Chimica Farmaceutica (Prima edizione), G. Costantino, G. Sbardella. Settembre 2024. ISBN: 978-8836231522

The aim of the course is to introduce the student to the main principles of medicinal chemistry. 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. 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.

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The course is given with the support of power point slides, which are given to the students at the beginning of the lessons. Moreover, the student will be introduced to the use of freeware softwares of molecular visualisation in order to handle and understand the chemical structures proposed during the lessons. Finally, practice exercises, with the aim of preparing the student to the exam, will be solved during the lessons.

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 For further informations, please refer to the course page on D.I.R. at: http://www.dir.uniupo.it 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.

The exam consists in a computer-based written test displaying questions (multiple choice). The exam aims at verifying both the knowledge on the contents of the course and the ability to apply this knowledge to specific cases of drugs used in therapy. The student has to demonstrate to be able to o identify the functional groups, the acid, basic and stereogenic centers, the plausible reactions of metabolism, the intermolecular interactions, 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 and the competence to apply the acquired knowledge and skills to specific concerns regarding the medicinal chemistry of the different classes of drugs.

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. The use of computer in drug discovery. Manipolation of chemical structures, conformational analysis, minimization, parametrization. The use of chemical and biological data banks, chemical similarity and X-ray structures. Ligand- and Structure-Based Drug Design. Virtual screening. De novo drug design. 3D-QSAR. Pharmacophore- Molecular docking, applications and drawbacks. Proteins. Resolution in 3D protein structures. Examples of protein purification. X ray cristallography. NMR spectroscopy. Co-cristallization. Quality of experimental data: resolution and B-factor. Protein Data Bank. On-line search of PDB. The structure of a .pdb. PyMol, main functions of the program. Basic procedure to visualize a .pdb in the PyMol software. 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. Examples of specific classes of drugs. Biotech drugs. Exercises.

The student at the end of the course will know the basic principles of medicinal chemistry, both in pharmacodinamics and pharmacokinetics. 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.