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 , ADMET )

G.L. Patrick Introduzione alla Chimica Farmaceutica (II Eds.) EDIses E. Stevens Medicinal Chemistry: The modern drug discovery process, Ed Pearson

The goals of the course of Medicinal Chemistry and Drug Design I are to introduce students to the key topics relating to medicinal chemistry and at the same time present and discuss general strategies for the drug design. Several drugs, with the aim of rationalizing their discovery will be discussed. At the end of the course, the student will have gain the essential stock of knowledge with regard to the drug design and the issues relating to their development. He/she will be also able to read, in a critical manner, scientific articles on medicinal chemistry.

Exam preparatory Organic Chemistry 2

The course consists of lectures with slides show.

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

The assessment of learning consists of a written test with open questions. The questions cover all the topics covered during the frontal teaching lessons.

Definition of Medicinal Chemistry, Pharmacodynamics, Pharmacokinetics. The concept of receptor. Receptor theory of Langley and Ehrlich. Definition of pharmacophore. Receptor theory of Fisher. Agonists, partial agonists, antagonists. Inverse agonists. Reversible antagonism, irreversible antagonistm, allosteric antagonism. Binding studies and the Scatchard plot. Dose-response curves for agonists. Effectiveness and affinity. Clarke Ariens and Stephenson receptor theories. The spare receptors. Dose-response curves for competitive antagonist. Theory of adaptation induced receptor. Receptor theory of the two-stage model. The enzymes. Acid-basic and nucleophilic catalysis mechanism. Reversible inhibitors, irreversible, allosteric. chemical functional groups useful for irreversible inhibition. Transition state inhibitors (examples). Suicide inhibitors (examples). Michaelis-Menten equation. Lineweaver-Burk equation. Competitive inhibitors, non-competitive, competitive, mixed. How drugs interact with receptors. Thermodynamics of interaction. The enthalpy and entropy contribution. Ionic bond. Hydrogen bond. Intramolecular hydrogen bond. Dipole-dipole interaction. Dipole-dipole induced. Covalent bond. Charge transfer. π -π interactions and π-cation. Halogen bond. Hydrophobic interactions. The chirality in drugs. Types of chirality. Definitions three-point Easson and Steadmann. hypothesis. Pfeiffer rule. eudismica analysis. Use of chirality in pharmaceutical chemistry. Chiral switch. Reverse enzymatic configurational, the case of ibuprofen. When to use a chiral drug. When to use a racemic drug. The problem of thalidomide. Lead discovery. Me-too compounds.. Functional groups to avoid. The problem of promiscuity. The problem of latent hits. Natural products. Amplification of the side effects. Fragment-based ligand design. Lead optimization. Pro-drug. Definition. Accidental Pro-drugs. Pro-drug in two stages, three stages, mutual pro-drug and pro-drug polymer. Pro-drug to improve the stability (examples). Pro-drug to prevent the metabolism of the first passage (example of bambuterol). Pro-drug to increase the duration of action (examples). Pro-drug to increase the solubility (examples). Pro-drug to improve the organoleptic characteristics (examples). Pro-drug to improve absorption (examples). Pro-drug to direct a drug (examples). Pro-drug to direct the drug in the CNS (examples). Pro-drug of alcohols, thiols and acids. Pro-drug for amides, imides and compounds with NH groups. Definition and examples of hard and soft drug. Isosterism and bioisosterism. Isosters of Langmuoir. Isosters of Grimm. Isosters of Erlenmeyer. The bioisostere concept. Classical and nonclassical isosters. Isosteric substitutions: H-D, H-F, F-OH, NH2-OH, OH-SH. The lethal synthesis. Divalent, trivalent and tetravalent isosteric substitutions. Non-classical bioisosteres of aromatic rings, esters, amides, carboxylic acids, phenols, catechols, carbonyls. isosters reversed. Isosterism carbon-silicon. The differences between silicon and carbon. Isosterism C-B and C-Se. Disjunctive approaches. molecular and simplifications on chiral centers.. Conjunctive approaches.. Introduction of cycles (see part on rigid analogues). Benzo-cracking or dissociation of the rings. Restructuring of cyclic systems. Introduction of new functional groups. Tactics. Change the distribution. Increase the metabolic stability. Synthesis of irreversible inhibitors. Functionalization of the aromatic rings. Repositioning of functional groups. Rational. Tactics. Vinilogy. Introduction, examples and rational method. Limits. Molecular doubling (twin-drugs). Rational and examples. The symmetry as a basis in the design of inhibitors of HIV protease. Molecular hybridization. Ideas, limitations. The concept of the balanced hybrid. Examples. Hybrids from the union of pharmacophoric groups of natural origin. The rigid analogues. Ideas, Benefits. Locate the active conformation. The case of acetylcholine, the case of dopamine. Stabilize a high energy conformation. Improve selectivity. Increase the power (the negative entropic effect). metabolic stabilization. Synthesis of partial agonists. Locate receptor subclasses. Examples. Disadvantages. Tactics. "Template" resistant to the hydrophobic collapse. QSAR (QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP) COMBINATORIAL CHEMISTRY

The students at the end of the course will know the key topics relating to medicinal chemistry and at the same time they will be able to present and discuss the general strategies for the drug design.