Day 1: Mon 12 Oct; 0900-1720

Chemistry and Pharmaceutical Industry, the new perspectives
Prof Bertrand Castro (Scientific Director Industrial Affairs, Sanofi-Aventis)
The importance of chemistry in Medicinal Research is well known; its involvement in Pharmaceutical Development is less popular and nevertheless necessitates an even higher degree of scientific inventivity in order to make the active molecules industrially feasible. The fundamentals of these two activities will be described and compared within the timelines of the project management of pharmaceutical R&D. Special attention will be given to the present status of the analytical characteristics of the Active Pharmaceutical Ingredients (APIs) concerning the genotoxic impurities. The importance of the physical characteristics of the APIs (polymorphism) will also be considered and the emergence of the supramolecular chemistry concepts in the formulation activities will be outlined. As a conclusion, the threats and opportunities open to chemistry within the Pharmaceutical Industry will be analysed.
Professor Bertrand Castro is an accomplished scientist in academia and industry. After 30 years of academic research carried out in the Faculty of Sciences in Paris, CNRS and the INSERM amongst others, he joined Sanofi in 1989 as R&D director for the chemical activities of the company. Prof Castro is currently Scientific Director for Industrial Affairs in Sanofi-Aventis. He has received a number of awards including the Silver medal (Chemistry) of the CNRS (1986) and the Highest Industrial Award of the French Chemical Society (1999).

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.
Recommended reading:
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 Ciaran Carolan (European Molecular Biology Laboratory Hamburg)
Almost 50% of drugs being used medicinally throughout the world today target the activities of the body’s myriad enzymes in order to exert their effects. As the human genome has recently been sequenced and the structures and functions of many more enzymatic proteins are being discovered, yet more targets for drug design are being noted and inhibitors of many of these enzymes will be the drugs of tomorrow.
In this lecture, the roles of the body’s numerous enzymes will be reviewed and the reasons why enzyme inhibition may be desirable will be enumerated. The structural basis of enzyme activity will be introduced, providing a basis for further understanding of the various methods employed to design new drugs – including in vitro and in silico methods. The relevance of these methods will be highlighted by providing examples of agents that are currently used, or otherwise are being developed for use, in the treatment of a number of important disease conditions.
Recommended pre-reading:
Hopkins A.L. and Groom C.R. (2002) The druggable genome. Nat Rev Drug Discov 9: 727-730. PMID: 12209152
Copeland R.A (2005) Why Enzymes as Drug Targets? in Evaluation of Enzyme Inhibitors in Drug Discovery; John Wiley, New Jersey.
Recommended follow-up reading
Praveen Rao P.N. and Knaus E.E. (2008) Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond. J Pharm Pharmaceut Sci 11(2): 81s-110s. PMID: 19203472
An J, Lee D.C., Law A.H., Yang C.L., Poon L.L., Lau A.S., Jones S.J. (2009) A novel small-molecule inhibitor of the avian influenza H5N1 virus determined through computational screening against the neuraminidase. J Med Chem 13;52(15): 4903-4910. PMID: 19419201
Patrick G.L. (2009) Anti-ulcer agents in An Introduction to Medicinal Chemistry, 4th Edition; Oxford University Press, Oxford.

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.
Recommended reading:
Myles D.C. (2003). Novel biologically active natural and unnatural products. Curr. Opin. Biotechnol. 14, 627-633. PMID: 14662393
Balunas M.J., Kinghorn A.D. (2005). Drug discovery from medicinal plants. Life Sci. 78, 431-441. PubMed Entry PMID: 16198377

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.
Recommended reading:
Searls, D.B. (2003). Pharmacophylogenomics: genes, evolution and drug targets. Nat. Rev. Drug Discov. 2, 613-623. PMID: 12904811
Neduva, V. et al. (2005). Systematic discovery of new recognition peptides mediating protein interaction networks. PLoS Biol. 3(12):e405. PMID: 16279839

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.

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.
Recommended reading:
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.
Recommended reading:
Lyne, P.D. (2002). Structure-based virtual screening: an overview. Drug Discov. Today. 7, 1047-1055. PMID: 12546894
Oprea, T.I. and Matter, H. (2004). Integrating virtual screening in lead discovery. Curr Opin Chem Biol. 8, 349-358. PMID: 15288243

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.
Recommended reading:
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. PMID: 12119609

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

Day 2: Tue 13 Oct; 0900-1720 
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.
Reference:
1.Lipinski, C.A. (2000). Drug-like properties and the causes of poor solubility and poor permeability, Journal of Pharmacological and Toxicological Methods, 44, 235-249
2.http://www.merck.com/mmhe/sec02/ch011/ch011b.html

Oral delivery of macromolecules: 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.
Recommended reading:
Books:
‘Drug Design and Development: Technology in Transition’ Ed. HP Rang (2006). Churchill-Livingston (Elsevier). ISBN 0443 064202.
 ‘Drug truths: dispelling the myths about Pharma R & D.’ LaMattina, JL (2009). Wiley. ISBN 978-0-470-39318-5.
Reviews
Transdermal drug delivery. Prausnitz MR, Langer R. Nat Biotechnol. 2008 Nov;26(11):1261-8. Review. PMID: 18997767
Orotransmucosal drug delivery systems: A review. Madhav NV, Shakya AK, Shakya P, Singh K. J Control Release. 2009 Aug 6. [Epub ahead of print] PMID: 19665039
Knocking down barriers: advances in siRNA delivery. Whitehead KA, Langer R, Anderson DG. Nat Rev Drug Discov. 2009 Feb;8(2):129-38. PMID: 19180106
Inhaled insulin--does it become reality? Siekmeier R, Scheuch G. J Physiol Pharmacol. 2008 Dec;59 Suppl 6:81-113. Review. PMID: 19218634

Patient Oriented Drug Delivery
Dr John Fox (Merrion Pharmaceuticals)
Ms Bozena Adamczyk (Merrion Pharmaceuticals)
(i) Key factors in patient oriented delivery, e.g. maintenance of efficacy, improvement of safety, convenience (frequency of administration, route etc) with examples from innovator products as well as reformulation exercises.
(ii) Role of formulation research in addressing the factors outlined above from the perspective of the formulation scientist.
Presenters
John Fox M.B.A., Ph.D. Chief Development Officer
Dr Fox has over 20 years experience in the pharmaceutical industry, mostly spent in the planning and development of new drugs to clinical proof of concept. As Chief Development Officer at Merrion, he is responsible for the coordination of activities taking Merrion’s portfolio of internal and partner projects into clinical development. Prior to joining Merrion, Dr Fox held a variety of operational and R&D positions in SME and multinational companies after starting his career as a member of the Dept. of Therapeutics and Pharmacology at Queens University, Belfast.

Bozena Adamczyk, M.Sc.(Pharm.), Formulation Scientist
Bozena Adamczyk has 9 years of experience in formulation of various solid, oral dosage forms. She received her master’s degree in pharmacy in 2001 from Jagiellonian University in Cracow, Poland. After completing her master, she worked as a formulation specialist for an international pharmaceutical company before joining Merrion as a formulation scientist. She is also pursuing PhD research as a part time postgraduate in the School of Pharmacy and Pharmaceutical Sciences, (TCD)

Lead optimisation: from active molecule to clinical candidate
Prof Mary J Meegan (School of Pharmacy and Pharmaceutical Sciences, TCD)
Lead optimisation is that part of the drug discovery process in which a defined lead compound (or series) is optimised to generate a drug candidate for preclinical development. The criteria to be fulfilled for promotion of a compound to drug candidate status vary from project to project. The major considerations include properties related to potency and selectivity, safety, toxicity and pharmacokinetics. The chemical aspects which are addressed include stability, chirality and ease of synthesis. The emphasis will be on current methods to generate pharmacokinetic and safety profiles of drug candidates, as well as how they must be balanced against one another for the best selection of appropriate drug candidates for further development. The pharmacological (ADME) and safety (toxicity) profiling aspects are covered separately. The ADME section covers the profiling of basic physicochemical parameters, such as solubility, and permeability as well as more complex traits such drug-drug interactions, metabolic clearance and protein binding properties.
Reference
Drug Discovery and Development, Ed. HP Rang, Elsevier, 2006
 
The Irish Clinical Trials Process
Siobhan Gaynor (MMI & ICRIN Senior Associate)
In Ireland, legislation governs clinical research involving medicinal products and research involving medical devices. In addition ethical considerations should abide by the current version of the Declaration of Helsinki as well as abiding by relevant data protection legislation. For all trials involving medicinal products and medical devices the explicit approval of the Irish regulatory Authority (IMB-The Irish Medicines Board) and relevant ethics approval must be sought prior to the commencement of any trial related activities.
References:
European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations, 2004 to 2006.
http://www.dohc.ie/legislation/statutory_instruments/pdf/si20060374.pdf?direct=1
http://www.dohc.ie/legislation/statutory_instruments/pdf/si20040878.pdf?direct=1
Guidance note for clinical investigators of medical devices
http://www.imb.ie/images/uploaded/documents/GN05-1_CIsCarriedOutinIreland.pdf 

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.
Recommended reading:
The Organic Chemistry of Drug Design and Drug Action; Richard B Silverman;
Elsevier Academic Press; 2004. 

Drug development: The industry perspective
Dr Damian O'Connell (Executive Director and Pain Therapeutic Area Development Team Leader, Pfizer)
Drug development is an expensive, long and high-risk business taking 10–15 years and is associated with a high attrition rate. It is driven by medical need, disease prevalence and the likelihood of success. Drug candidate selection is an iterative process between chemistry and biology, refining the molecular properties until a compound suitable for advancing to man is found. Typically, about one in a thousand synthesised compounds is ever selected for progression to the clinic. Prior to administration to humans, the pharmacology and biochemistry of the drug is established using an extensive range of in vitro and in vivo test procedures. It is also a regulatory requirement that the drug is administered to animals to assess its safety. Later-stage animal testing is also required to assess carcinogenicity and effects on the reproductive system. Clinical phases of drug development include phase I in healthy volunteers to assess primarily pharmacokinetics, safety and toleration, phase II in a cohort of patients with the target disease to establish efficacy and dose-response relationship and large-scale phase III studies to confirm safety and efficacy. Experience tells us that approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Each drug must demonstrate safety and efficacy in the intended patient population and its benefits must outweigh its risks before it will be approved by the regulatory agencies. Strict regulatory standards govern the conduct of pre-clinical and clinical trials as well as the manufacturing of pharmaceutical products. The assessment of the new medicinal product’s safety continues beyond the initial drug approval through post-marketing monitoring of adverse events.
References
Tufts Center for the Study of Drug Development pegs cost of a new prescription medicine at $802 million. 2001. http://csdd.tufts
Drug development: the short story 7. Cost of drug development. Network Science Corporation. http://www.netsci.org/  
Drugresearch. com: drug development costs hit $1.7 billion. 2003. http://www.drugresearcher.com /Research-management/Drugdevelopment- costs-hit-1.7-billion
Kola I, Landis J: Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004;3:711–715.
Dutta A: Discovery of new medicines; in Griffin JP and O’Grady J (eds): The Textbook of Pharmaceutical Medicine. London, BMJ Books, 2002, .
Biomarkers Definitions Working Group: Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69: 89–95.
Information detailing the story of how the well-known medicine, Viagra, was researched and developed. http://resources.schoolscience.co.uk/pfizer/viagra/index.html
Information on how medicines are researched and developed by GlaxoSmithKline scientists. http://www.gsk.com/research/about/index.html 
 
Commercialisation (Agreements in the Life Sciences Sector)
Mr Colin Sainsbury (BCM Hanby Wallace)
Collaboration as between life sciences companies and/or with research institutions is the life blood of the life sciences sector. The presentation covers the key issues that need to be considered in relation to the conclusion of preliminary agreements (such as confidentiality and material transfer agreements, option agreements), through to substantive licence and development agreements.
Even at a relatively early stage of its development, an Irish life sciences company may be involved in complex and heavily negotiated in-licence and out-licence agreements. The importance of concluding the right agreement is critical to such a company given the impact of such an agreement on its core technology and the fact that such an agreement may be in force for a long number of years.
Colin Sainsbury has significant experience in the life sciences sector, Colin was general counsel of Elan's drug delivery business. Since joining BCM Hanby Wallace in 2004 Colin has represented a large number of Irish and international research and commercial organisations in relation to the in-licensing and out-licensing of intellectual property in the life sciences sector.

Concluding Remarks
Dr Marc Devocelle (RCSI)  
This lecture will conclude the course by providing selected key figures in drug discovery and development and present some recent examples of successful drug candidates. These selected case studies will introduce some concepts such as personalised medicines, attrition rates of drug candidates by disease areas and issues that lead to drug failure in the clinic but will essentially illustrate that successful drugs do not always comply with 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.