Corso di laurea magistrale in Chimica Clinica Forense e dello Sport

Module A:
The drug discovery pipeline and the role played by the pharmacokinetic phase on it.

Module B:
Learning the chemical structure-activity relationships of the compounds and overview of the main biologically active compounds in the context of doping in sport and abuse. Acquisition of skills relating to the identification of pharmacologically active molecules and their pharmacodynamic and pharmacokinetic properties.

Module A:
Acquisition of the concept  of the multidisciplinarity and interdisciplinarity of the drug discovery process. Knowledge of some of the main pharmaceutical methodologies used in drug discovery and drug development.

Module B:
Acquisition of the concepts of bioactive molecule and its characterization parameters.

Theoretical lessons including multimedia material

Written examination which could be divided in two parts (module A and B). The exam is devoted to the assessment of the knowledge, and related understanding of the program attained by the students. In addition, also knowledge and understanding of basic knowledge in Chemistry which should be necessary consider will be evaluated, as well as the use of a proper  scientific/technical language. Rating of thirty-mediated (with tolerance in excess) between the two modules.

The chemical structure and its relevance in drug discovery. Databases of common usage: Chemicalize, Chemspider, ChEMBL.

List of drugs for which the chemical structure has to be known (module A). Basic concepts: drug definition, the three drugs action phases, the significance of ADME. Physiological barriers governing drug exposure: cell membranes, gastrointestinal barriers, barriers in the blood stream with emphasis on drug/albumin interaction, barriers in the liver. Pathological barriers limiting drug exposure: mucus in cystic fibrosis. How drugs pass cell membranes: passive diffusion vs transporter mediated, transporters with care for P-glycoprotein. In vivo pharmacokinetics: plasmatic drug concentratio vs time plots as a result of a single iv and oral administration. Definition of the main pharmacokinetic parameters (clearance, distribution volume, half-time and bioavailability) and their determination from plasmatic drug concentratio vs time plots. In vitro ADME:  in vitro tests to determine surrogates of pharmacokinetic parameters. The QSPR concept. The main molecular properties and their descriptors in ADME: molecular weigth, ionization, lipophilicity, polar surface area, solubility. Application: www.chemicalize.org to determine molecular descriptors.

How a molecule becomes a drug: the pharma industry pipeline. The drug discovery process: definition, keywords, the (Q)SAR concept, steps. The main strategies to discover hit/lead compound. Phenotypic e target-based screening. Lead optimization. Tools to predict the probability of success of candidates in early drug discovery: the Lipinski Rule of 5 (Ro5), the Biopharmaceutics Classification System (BCS), the lipophilicity efficiency (LipE). Application: strategies to obtain a lead compound in the discover of antidiabetics drugs. How rules of thumb improved the success of pharma programs in the recent years. New strategies to improve the balance solubility/permeability. 

Preclinical research: the main routes of delivery, drug delivery systems (DDS) and drug delivery and targeting systems (DDTS) . DDS application: piroxicam and beta-cyclodextrins. DDTS application in anticancer therapy: Myocet e Doxil. Drug formulation: dosage forms classification, the excipients and their classification. The IND (Invegational New Drug Application) application. Clinical trials: definition and characterization of Phases I, II, III e IV. PK/PD modeling. Biotechnological drugs: definition, the technology of the DNA recombinant. Biotechnological vs common drugs. Generic and biosimilar drugs.

In silico tools: molecular descriptors calculation (pKa, log P/log D, PSA), QSAR/QSPR methods and their application, virtual screening: ligand-based (pharmacophore searching) and structure-based (docking) approaches. The various steps of a pharmacophore searching. Docking: the docking and the scoring steps, the pros and cons of the method. Experimental tools. In vitro assays. Methods to measure molecular descriptors: pKa (potentimetric, spectrophotometric, electrophoretic, HPLC), log S (shake-flask), log P/ log D (shake-flask, potentiometric, chromatographic). Methods to measure in vitro ADME properties: permeability (IAM, PAMPA). Methods to measure drug/macromolecule interactions (dyalisis, stopped flow, surface plasmon resonance, chromatographic approach). Cell-based methods to measure permeability. Methods to be used on animal models: the Zebrafish model, Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET).

Drugs and drug targets. Definition of drug (FDA). Neurotransmitters. Drug targets. Receptors classification. Protein-ligand interaction. Intermolecular interactions. Affinity vs intrinsic activity (or efficacy) vs potency. The dose-response curve. Agonists and antagonists. How to obtain EC50. Biological pathways and networks. Specificity vs. Selectivity. Therapeutic index.

General concepts. Prodrugs. Reactions catalysed by metabolic enzymes. Drug metabolism and toxicity. Enzyme induction and inhibition. Cytochrome P450, structure and cycle. Phase 1 reactions. Phase 2 reactions. How to evaluate the metabolic profile of a drug candidate.

Brain penetration: concepts and misconcepts. The Blood Brain Barrier (BBB). The Blood Cerebrospinal Fluid Barrier (BCSFB). Parameters: the unbound drug concentration in the brain, the unbound brain to plasma ratio, the total brain to plasma ratio, the BBB passive permeability, the efflux ratio. Misconceptions in the design of central active compounds. Tools related to the discovery of active CNS compounds. Measurement and prediction of fu. In silico tools to predict BBB penetration. In vitro tools to determine BBB passage.

Definition of doping and WADA. No CNS drugs. Drugs acting on adrenergic receptors. Adrenergic receptors. Beta-2 agonists. Beta-blockers. Non-selective beta antagonists. Selective (cardiac) beta-1 antagonists. Mixed alpha/beta antagonists. Drugs affecting inflammation mediators. Inflammation: chemical mediators. Prostaglandins and leukotrienes. Histamine. Histaminergic receptors. NSAIDs. NSAIDs gastrophathy. COX-1/COX-2 selectivity. Paracetamol. Salycilates. Arylacetic acids. Arylpropionic acids. Piroxicam. Oxibs. Sulphonamides. Bioisosters. SAIDs. The endogeneous mechanism. Glucocorticoids. H1 antihistamines. 1st generation. 2nd generation. 3rd generation. hERG toxicity. Diuretics. Osmotic diuretics. Carbonic anhydrase inhibitors. High-ceiling (Henle’s loop) diuretics. Thiazides. Potassium-sparing diuretics. Diuretics and doping. Sex hormones. Steroids. Androgens. Estrogens. Progestogens. Doping agents: nandrolone and stanozolol. Designer steroids. CNS drugs. Pathologies classification. NIDA. Antipsychotics. Dopamine. Serotonin. Classic and atypical antipsychotics. Anxiolytics. GABA. Benzodiazepines. Imidazopyridines. 5-HT1A agonists. Sedative-hypnotics. Barbiturates. Psychotomimetics. Cannabinoids receptors. Glutamate. Cannabinoids. LSD. Psychotomimetics Ar-C-C-N. Stimulants. Amphetamine. Ephedrine. Cocaine. Xanthines. Narcotics and analgesics. The self-reward system. Morphine. Opioids: μ-agonists and antagonists.

The need of implementing Intramolecular Hydrogen Bonding (IMHB) considerations in drug discovery and how to do it. European Pharmacopeia (EP): analytical determination of benzocaine, xanthines, quinine hydrochloride.