Ateneo - UPO

Definition of pharmaceutical chemistry. Absorption. Metabolism. Bonds involved in the interaction with the site of action. Role of stereochemistry in the interaction with the site of action. Possible targets of a drug. Receptors as drug targets. Enzymes as drug targets. Miscellaneous. Drug discovery. Hit compound and lead compound. Identification of hit and lead compounds. Identification of drug-like molecules. Drug optimization. Optimizing interaction with the target. Optimizing access to the target.

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; E. Stevens, Medicinal Chemistry: The Modern Drug Discovery Process, Pearson.

1. Knowledge and understanding At the end of the course, the student will know and understand the basic concepts of pharmaceutical chemistry, particularly the path followed by a drug in the body, from the pharmaceutical phase to the pharmacodynamic phase. The student will also be introduced to the strategies underlying drug discovery, drug design, and drug development. 2. Ability to apply knowledge and understanding For both the drugs specifically covered and related compounds, the student will be able to apply the acquired knowledge and understanding to the recognition of structures, the discussion of their chemical and physicochemical properties, their mechanism of action and the relationship between structure and biological activity, their metabolic properties, and the proposal of possible synthetic routes for their production. 3. Management of acquired knowledge to make judgments The student will be able to express informed judgments related to structure–activity relationships, metabolism and related toxicity, production, and drug–drug interactions. Furthermore, the student will be equipped with the tools needed to critically assess texts and scientific articles in the field of pharmaceutical chemistry. 4. Communication skills The student will develop the ability to clearly and, when possible, originally present a topic covered during the course, and to respond appropriately to questions, criticisms, and suggestions. 5. Learning skills The student will develop the ability to dynamically and as independently as possible manage their own knowledge in the field of medicinal chemistry.

Passing all first-year exams is a prerequisite for all third-year exams. Knowledge of biochemistry, physiology, and pathology is necessary for a full understanding of the course.

The course consists of lectures supported by slides, which are provided to students at the beginning of the course. Both general and specific topics will be presented, offering the essential knowledge needed to understand the subject matter. The course also aims to encourage discussions with students, illustrating how to develop transferable skills across different drug classes—such as predicting the chemical and physicochemical properties of drugs based on their structure, identifying key structural elements involved in the mechanism of action, and recognizing alert groups that may lead to toxic effects. At the end of each module, blackboard exercises will also be conducted to help students prepare for the exam.

Students with disabilities, Specific Learning Disorders (SLD), or Special Educational Needs (SEN) can request dedicated services and tools by contacting the Career Development and Student Services Staff and by consulting the dedicated page on the University website: https://uniupo.it/it/servizi/servizi-studenti-disabili-e-dsa Once they have contacted the University Staff, students with disabilities, SLD, or SEN may also get in touch with the course instructor to discuss exam arrangements and other teaching-related aspects.

The exam consists of a written test with theoretical questions covering the course content from a knowledge-based perspective. Some questions focus on a drug molecule whose chemical structure is provided by the instructor; students are expected to identify acidic, basic, and stereogenic centers, intermolecular interactions, possible metabolic reactions, compliance with Lipinski's rule, and so on. To pass the exam, the student must correctly answer more than half of the questions. These assessments aim to verify that the student has achieved the learning objectives in terms of knowledge and understanding of the content, the ability to clearly and accurately explain concepts, and the ability to apply the acquired knowledge and skills to specific problems related to the chemical and pharmaceutical aspects of the drug classes covered.

Definition of Pharmaceutical Chemistry Absorption Mechanisms of absorption. Passive transport. Partition coefficient. Fick’s law. Ion-pair transport. Carrier-mediated transport. Vesicular transport. Paracellular transport. Absorption via the oral route: first-pass metabolism. Distribution Binding to plasma proteins. Metabolism Phase I and Phase II metabolism. Effects of metabolism. Soft and hard drugs. Bonds involved in drug–target interactions Covalent bond. Ionic bond. Dipole–dipole and ion–dipole interactions. Hydrogen bond. Halogen bond. Charge transfer. van der Waals interactions. Hydrophobic interactions. Pi–pi interactions. Role of stereochemistry in drug–target interaction Three-point contact model. Pfeiffer’s rule. Eutomer, distomer, eudismic ratio. Chiral switch. Methods for obtaining enantiomerically pure drugs. Possible drug targets Structurally specific and nonspecific drugs. Receptors as drug targets. Enzymes as drug targets: inhibitors acting on the active site, reversible inhibitors (competitive and non-competitive), irreversible inhibitors, transition state analogs, suicide inhibitors. Miscellaneous Drugs targeting transport proteins. Drugs targeting structural proteins. Drugs interfering with protein–protein interactions. Drugs targeting lipids. Drug discovery Hit compound and lead compound. Selecting the disease, the target, the biological assay. High-throughput screening, NMR-based screening, virtual screening. Parallel and combinatorial synthesis. Lead compound identification Natural products, serendipity, modifications of natural ligands, me-too drugs, SOSA (Selective Optimization of Side Activities) approach, screening of compound libraries, de novo drug design, fragment-based drug design. How to identify drug-like molecules Lipinski’s and Veber’s rules. Drug optimization Optimizing interaction with the target: structure–activity relationships, isosterism and bioisosterism (classical and non-classical bioisosteres), pharmacophore identification, various drug design strategies (structure extension, chain extension/contraction, homology, vinylogy, benzology, ring expansion/contraction, ring variations, ring fusion, structure simplification, structure rigidification, conformational blockers, twin drugs and hybrids). Optimizing access to the target: Improving hydrophobic/hydrophilic properties, increasing or decreasing resistance to chemical or enzymatic degradation, prodrugs, mutual prodrugs. Blackboard exercises with examples of drug molecules Recognition of functional groups, acidic, basic, and stereogenic centers, possible intermolecular interactions, potential metabolic reactions, etc.

The student will have learned the basic principles of pharmaceutical chemistry, from pharmacokinetic to pharmacodynamic aspects, which will be further explored in the subsequent courses on Anticancer Drugs, Antimicrobial Chemotherapy, and Special Pharmaceutical Chemistry, where different drug classes will be addressed. The student will also be able to apply these general principles to a drug molecule, assessing its chemical, metabolic, and drug-likeness properties. Furthermore, they will have understood the role of pharmaceutical chemistry in the drug discovery and drug design processes, as well as the strategies that can be implemented to improve a molecule’s pharmacokinetic and pharmacodynamic properties.