Drugs Chemistry

Biology and Chemistry knowledge

Theoretical Matrix:

Essentially expository methodology using the appropriate audiovisual means.

Theoretical-practical matrix: Exercises to apply some theoretical contents.

Analysis and discussion of scientific articles where the themes developed in the theoretical matrix are discussed and deepened.

Design of chemical structures with specific programs and free access. Visualization of molecular modeling programs available for free.

Laboratory work.

Students should acquire knowledge of the study of drugs from a chemical point of view as well as the basic principles used in its design and development

Theoretical matrix:    

1 – Introduction to Chemistry of Drugs: (8 H)

Drugs and Medicinal Chemistry. Therapeutic Index. Intermolecular binding forces: electrostatic, Hydrogen bonds, Van der Waals interactions, dipole-dipole  and ion-dipole interactions.

Fundamentals of stereochemistry: Isomerism

Classification and nomenclature of drugs.

Pharmacodynamics

Pharmacokinetic: Drug absorption, drug distribution, drug metabolism (Phase I and Phase II transformations; the cytochrome P450 enzimes; Flavins monooxygenase and other enzymes, drug excretion)

2- Drug targets: (10H)

-Proteins – structure.

Structural and transport proteins as drug targets. Peptids or proteins as drugs (Hormones, peptides, recombinant enzymes and monoclonal antibodies).

Enzymes: Reversible and irreversible Inhibitors. Halosteric Inhibitors. Selective isoenzyme inhibitors. Medicinal uses.

– Receptors. Receptor types and subtypes. Neurotransmission. Activation of membrane receptors (G protein-associated receptors, ion channels and kinase-linked receptors) and intracellular receptors activation. Drugs and  receptors: The Design of  agonists, antagonists and partial agonists. Allosteric modulators

-Nucleic acids (DNA): fundamentals of structure and function. 

Drugs that act on DNA: Intercalating drugs acting on DNA; Topoisomerase poisons; Alkylating and metallating agents; Chain cutters; Chain terminators. Controllers of gene transcription.

-Nucleic acids (RNA): inhibitors of translation; Antisense therapy.

-Lipids and Carbohydrates:

Drugs that act on lipids: disturbing membrane, ‘Tunnelling molecules’ and  ion carriers.

Drugs that acts on carbohydrates: antigens and antibodies, cyclodextrins.

3- Drug discovery, design and development.(6H)

Drug discovery: finding a lead (Choosing a disease, Choosing a drug target). Models

Finding a lead compound: Screening of natural products (Plant kingdom, Microorganisms, Marine sources, Animal sources, Venoms and toxins). Examples.

Screening synthetic compound ‘libraries’. Existing drugs (‘Me too’ and ‘me better’).

Enhancing a side effect: SOSA approach—Selective Optimization of Side Activities). Examples.

Drug design: optimizing target interactions. Structure-activity relationships (SAR).

Binding role functional groups: alcohols and phenols, aromatic rings. Models.

Binding role of alkenes, ketones, amines, amides, carboxylic acids, esters, halides and ethers.

Isosteres. Models.

Identification of a pharmacophore.

Drug design: optimizing access to the target.

Optimizing hydrophobic/hydrophilic properties: Varying logP; Varying polarity; Varying N-substituents. Models.

Making drugs more (or less) resistant to chemical and enzymatic degradation: Steric shields, Stereoelectronic modifications, Removal or replacement or introduction of susceptible metabolic groups. Models.

Reducing toxicity. Prodrugs to improve membrane permeability. Prodrugs to prolong drug activity. Prodrugs masking drug toxicity and side effects. Optimization of water solubility. Models.  

4- Computers in medicinal chemistry. (6 H)

Computers and chemistry in drug development. Drawing chemical structures. Molecular properties, Conformational analysis, minimizing energy,  overlapping structures.  

Identifying the active conformation and the pharmacophore. Docking procedures.

Quantitative structure-activity relationships (QSAR): Graphs and equations, Physicochemical properties, Electronic effects, Steric factors. 

General procedures; advantages and assumptions. Models validation.

Theoretical-Practical Matrix: Main routes of drug administration.

Issues related to drug dosage (dosage, dosage and formulation vs route of administration, half-life, AUC curve).

Notions of chirality of drugs and their importance. (Bases of isomerism).

Octanol / water partition coefficient

Laboratory work:

“The influence of pH on drug absorption”

“Experimental Determination of logP”

Access to sites on the Internet where you can deepen the themes developed.

Contact with some programs for the design of chemical structures and determination of molecular properties used in chemistry that are freely accessible online.

NAO

Main Bibliography

• PATRICK, Graham L. ; SPENCER, John – An introduction to medicinal chemistry. 7th ed.. Oxford ; New York : Oxford University Press, cop. 2023. xxii, 960 p.. ISBN 978-0-19-886666-4
• BARREIRO, Eliezer J. ; FRAGA, Carlos Alberto Manssour – Química medicinal  : as bases moleculares da ação dos fármacos. 2ª ed. Porto Alegre : Artmed, 2008. 536 p. ISBN 978-85-363-1205-7.
• SILVERMAN, Richard B. – The organic chemistry of drug design and drug action. 2nd ed. Amsterdam [etc.] : Elsevier Academic Press, 2004. xix, 617 p. ISBN 978-0-12-643732-4

Secondary Bibliography

• Pinto, Madalena, Manual de trabalhos laboratoriais de Química Orgânica e Farmacêutica, Lidel- edições técnicas, lda, 2011. 484p. ISBN: 978-972-757-750-7