Day 1

From genes to drugs
Dr Marc Devocelle (Department of Pharmaceutical Chemistry, RCSI)
This lecture will set the scene for the course by giving an overview of the drug discovery process and its associated techniques and principles. Introduction to the targets of drugs, their identification (including genomic approach) and validation, the optimisation of drug leads and clinical development of drug candidates will be highlighted by some recent examples in drug development. These selected case studies will also present concepts such as personalised medicines, attrition rates of drug candidates by disease areas and issues that lead to drug failure in the clinic. In addition, they illustrate that successful drugs do not always comply to the classical process and principles of modern drug discovery…
Further reading:
[1] Drews J, “Drug Discovery: A Historical Perspective”, Science, 2000, 287, 1960-1964
[2] Drews J, “Case histories, magic bullets and the state of drug discovery”, Nature Reviews Drug Discovery, 2006, 5(8), 635-640.
[3] Bleicher KH, et al, “Hit and lead generation: beyond high-throughput screening”, Nature Reviews Drug Discovery, 2003, 2(5), 369-378.
[4] Kling J. “From hypotension to angina to Viagra”, Modern Drug Discovery, 1998, 1 (2), 31, 33-34, 36, 38.

Molecular basis of drug action: drug receptor interactions
Dr Isabel Rozas (School of Chemistry, TCD)
To obtain a pharmacological response, a complex between the drug molecule and its site of action should be formed. The component of the organism with which the drug interacts is designated the receptor and there are several groups of receptors distinguished on the basis of chemical suprastructure including: proteins, enzymes and nucleic acids. The formation of this drug-receptor complex and, the interactions established within this complex, initiate a number of biochemical and physiological changes that are associated to the response of the drug. An overview of the most characteristic chemical interactions established between drug and receptor will be presented.
Reference
An Introduction to Medicinal Chemistry. Graham L. Patrick, Editor. Oxford University Press. 2005. ISBN 0-19-927500-9

Molecular basis of drug action: catalytic receptors, enzymes and their inhibition
Dr John Gilmer (School of Pharmacy & Pharmaceutical Sciences, TCD)
Almost half of all clinically used drugs target enzymes. Analysis of the human genome for potential targets for drugs indicates that enzyme inhibitors will continue to dominate the drug development scene. The objectives of this lecture are a) to survey enzyme inhibitor drugs and explain why enzymes are attractive drug targets; b) to review some features of enzyme action that are important to understand in the context of drug design and; c) to outline commonly used strategies in enzyme inhibitor design. The molecular mechanism of action of some clinically relevant drugs will be used as illustration.
Reference
Hopkins A.L. and Groom C.R. (2002) The druggable genome. Nat. Rev. Drug. Discov. 9, 727-730. PubMed Entry

Natural products as leads in drug design
Dr James Barlow (School of Pharmacy, RCSI)
This lecture will explore the diversity of natural products, and the application of molecules isolated from natural sources (plants, bacteria, fungi and animals) both as drugs and as lead compounds in drug discovery. Modern pharmacognostical and phytochemical methods including high-throughput screening will be included. Some case studies will be explored in detail.
References
Myles D.C. (2003). Novel biologically active natural and unnatural products. Curr. Opin. Biotechnol. 14, 627-633. PubMed Entry
Balunas M.J., Kinghorn A.D. (2005). Drug discovery from medicinal plants. Life Sci. 78, 431-441. PubMed Entry

Day 2

The concept of pharmacophore: biological perspective
Prof Niamh Moran (RCSI)
This lecture builds on the previous one, illustrating with examples of peptides and peptidomimetics that have been developed as drugs, and highlighting areas for concern in such development. Using the cardiovascular system as an example, the development of a simple peptide-based drug (namely RGD; an integrin receptor ligand) will be reviewed focusing on experimental analysis of the pharmacophore. The targeting of intracellular ligands using cell-permeabilizing delivery agents will be discussed. Finally, a summary of the time involved in biological screening and verification will be presented.

The concept of pharmacophore: informatics perspective
Prof Denis Shields (UCD Conway Institute of Biomolecular & Biomedical Research
An evolutionary perspective on drug design allows consideration of how conservation can be used to define targets, of how specific a drug is for one of a number of human proteins, and of how relevant animal models might be to the human clinical setting. Much of molecular modeling concentrates on finding a drug that fits a pocket in the protein structure. An alternative approach finds activities within stand-alone short protein sequences, which may act as oligopeptide drugs or may serve as models for drug design.
References
Searls, D.B. (2003). Pharmacophylogenomics: genes, evolution and drug targets. Nat. Rev. Drug Discov. 2, 613-623. PubMed Entry
Neduva, V. et al. (2005). Systematic discovery of new recognition peptides mediating protein interaction networks. PLoS Biol. 3(12):e405. PubMed Entry
 

Day 3

Rational drug design: structure/activity relationships
Dr Isabel Rozas (School of Chemistry, TCD)
The activity of a drug is a consequence of the interactions established between that drug and a receptor, therefore it can be concluded that the activity of a drug and its chemical structure are intimately related. The concept of quantitative drug design is based on the fact that the biological properties of a compound are a function of its physicochemical/structural parameters, which have a profound influence on its chemistry. Quantitative-Structure Activity Relationship methods intend to relate the chemical structure of a drug with its biological activity by means of a mathematical equation using a number of parameters to describe the structure/properties of the drug.
References
Predicting Chemical Toxicity and Fate. Edited by Mark T. D. Cronin and David J. Livingstone. CRC Press, Boca Raton, FL. 2004. ISBN 0-415-27180-0.
Chemoinformatics in Drug Discovery. Methods and Principles in Medicinal Chemistry. Volume 23. Edited by R. Mannhold, H. Kubinyi, and G. Folkers. Wiley-VCH Verlag GmbH, Weinheim, Germany. 2005. ISBN 3-5273-0753-2. 

Rational computer-aided drug design
Dr Darren Fayne (Molecular Design Group, School of Biochemistry and Immunology, TCD)
Rational computer-aided drug discovery is typically addressed from two perspectives; structure-based, when the 3D structure of the protein target receptor is available, and ligand-based, when such a structural representation is absent. These approaches are utilised in virtual screening programs to identify active structures or potential hits from databases of drug-like compounds and to prioritise lists of compounds for biological screening, and are often highly complementary. When used before in vitro experimental screening, in silico screening focuses the discovery process, considerably reducing costs and improving timelines. This lecture will discuss the advantages and limitations of utilising computational techniques in the quest for new therapeutic ligands.
References
Lyne, P.D. (2002). Structure-based virtual screening: an overview. Drug Discov. Today. 7, 1047-1055. PubMed Entry
Oprea, T.I. and Matter, H. (2004). Integrating virtual screening in lead discovery. Curr Opin Chem Biol. 8, 349-358. PubMed Entry

Techniques in rational drug design: X-ray crystallography & NMR
Dr Amir Khan (School of Biochemistry and Immunology, TCD)
Structure-based drug design can accelerate the process of drug discovery and significantly reduce associated costs. The two most common techniques for determining three-dimensional structures of protein targets for drugs are X-ray crystallography and nuclear magnetic resonance spectroscopy. Novel high-throughput technologies in drug discovery that utilize these techniques will be discussed.
Reference
Blundell, T.L., Jhoti, H. and Abell, C. (2002). High-throughput crystallography for lead discovery in drug design. Nature Rev. Drug Discov. 1, 45-54. PubMed Entry

Case studies in drug design and development
Prof Mary J Meegan (School of Pharmacy and Pharmaceutical Sciences, TCD)
The practical and theoretical approaches to modern drug discovery will form the core of this lecture topic. For many small molecule drugs a combination of both structure and ligand based techniques are utilized in the design of new molecular scaffolds and in the optimization of the structures and properties of lead compounds for development as clinical drugs. An overview of the various strategies employed will be presented and illustrated with specific case study examples from the areas of anticancer, cardiovascular and antidepressant drugs to ensure a range of disease areas, different structural types of active compounds and different discovery processes.
References
The Organic Chemistry of Drug Design and Drug Action; Richard B Silverman;
Elsevier Academic Press; 2004. 

Day 4

The role of drug delivery in drug design and development
Dr Sally-Ann Cryan (School of Pharmacy, RCSI)
Many promising and highly active new drugs never go beyond the laboratory because of problems associated with their formulation and delivery. The structure of drugs not only affects their pharmacological activity but also their pharmaceutical and pharmacokinetic properties. This lecture will serve as an introduction to the impact of drug structure and design on a molecule’s pharmaceutical properties (e.g. solubility and stability) and ultimately on its’ pharmaceutical development into a final product. An overview of the main routes of administration, dosage forms and excipients used in drug delivery will be provided.

Delivery of protein-based therapeutics: challenges and opportunities
Prof David Brayden (UCD School of Agriculture, Food Science, & Veterinary Medicine and UCD Conway Institute)
Biopharmaceuticals including peptides are normally injected, causing inconvenience to patients and high costs to healthcare systems. Technologies to overcome the epithelial permeability barrier of the intestine, the rate-limiting step for peptide oral delivery, will be discussed.

Drug distribution and targeting
Prof. Caitriona O’Driscoll (UCC)
Abstract: Following administration of a drug, for example by the oral route, the drug is absorbed across the epithelial barrier into the blood compartment. It is then distributed around the body to various tissues including the target site of action. The advantages of targeted delivery include a reduction in side effects by ensuring access only to the diseased/affected cells and avoiding healthy tissue, thereby resulting in a more efficient therapeutic response. The majority of drugs are metabolised before excretion or elimination, for most drugs metabolism mainly occurs in the liver. Finally the drug is excreted/eliminated from the body principally via the kidney into the urine. The absorption, distribution, metabolism and elimination of a drug are referred to collectively as the ADME profile. The factors influencing the ADME profile of a drug including; the physicochemical properties of the drug, the physiological environment following administration, and, finally the design of the formulation or drug delivery system will be discussed.

Gene Delivery: from molecular packaging to targeting
Prof. Caitriona O’Driscoll (UCC)
Concepts of bioconjugates and their uses in drug delivery. Some standard chemical linker molecules for attaching sugars, PEG, folate, and the strategies for using them.
Concepts of gene therapy: gene delivery, RNA interference. Synthetic gene delivery vectors - advantages over viral vectors, disadvantages. How commercial vectors work in vitro – obstacles to in vivo delivery and a critical look at the state of the art. Using a new series of vectors based on cyclodextrins as a case study, a look at the techniques involved in trying to develope better vectors and formulations.