The Fundamentals of Drug Discovery
Drug discovery is highly multidisciplinary in nature and you will need to be scientifically multi-lingual to be able to fully understand its practice. This module considers the following key areas:
- A History of Drug Discovery
- Modern Day Drug Discovery
- Target Identification and Validation
- Hit and Lead Identification
- Screening Compound Libraries
- Lead Optimisation
- Developing a drug from a lead
- Case studies and workshops
- Organic Synthesis
A History of Drug Discovery: These lectures explore the historical development of the pharmaceutical industry and the regulatory bodies using numerous examples of successfully launched drugs to illustrate the timeline.
Modern Day Drug Discovery: Lectures describe the overall journey from concept to clinic in broad terms, providing a very introductory exposure to market analysis and target selection, lead discovery and lead optimisation, clinical trials and the NDA to launch.
Target Identification and Validation: These lectures will provide an overview of different types of biological target, and how they link to disease as well as important screening approaches/technologies in use. Key considerations for measuring and quantifying both ligand affinity and biological response will be explored. The importance of target validation will also be discussed.
Hit and Lead Identification: After an overview of the drug discovery process, a range of sources for ‘hits’ and ‘leads’ will be considered, including the use of synthetic libraries.
Screening Compound Libraries: Building on earlier concepts in the module this series of lectures will tackle a range of screening techniques (e.g. high throughput, fragment-based, virtual libraries) and how to identify high quality hits.
Lead Optimisation: Once the starting point of a drug discovery campaign has been identified, there are a number of key considerations for the lead optimisation phase of drug discovery. We will consider the types and importance of specific molecular interactions between ligands and their targets and tools used to identify Structure-Activity Relationships (SARs). Key physicochemical properties and parameters of importance during the optimisation phase will be explored further, as well as medicinal chemistry strategies that can be employed.
Developing a drug from a lead: This final series of lectures will cover the process involved in moving from an optimised lead to a marketable drug.
Case studies and workshops: All the major themes in the module are illustrated with a number of detailed case studies. The underlying fundamental principles relating to molecular interaction, physicochemical properties and medicinal chemistry will be tackled through a problem-based format in a workshop setting.
Organic Synthesis: This series of laboratory sessions introduces you to practical organic chemistry through the synthesis and purification of a currently marketed drug. You will apply the theoretical considerations of functional group reactivity and physicochemical properties you have encountered in lectures and have the chance to practice fundamental techniques in synthetic organic chemistry, compound purification and analysis.
Drug Targets and Pharmacodynamics
A primary theme within this module is identification of how the major classes for drugs in current clinical usage are exploited. To facilitate that, there are several subthemes:
- Design and analysis of experiments and the search for reproducibility
- Communication of scientific information
- Quantitation of drug effects
- The Diversity of Molecular Drug Targets
- Cell Signalling Modalities and Their Relationship with Tissue and Organismal Behaviours
- Pharmacotherapy of Major Human Diseases and Disorders
Teaching on this module is delivered through a mix of lectures, workshops, practicals and slidecasts.
Drug Discovery and Development 1
We put into practice key concepts learned in Fundamentals of Drug Discovery. This module considers the following key areas:
Lead Compound Identification: An in depth look at strategies employed in hit to lead; includes HTS, natural products, parallel synthesis strategies, diversity and biology oriented synthesis, fragment based drug discovery, in silico screening and computational modelling, lead-likeness and drug-likeness analysis
Primary Exploitation of SAR: An in depth look at how to undertake structure activity relationships with analysis through synthetic medicinal chemistry; includes a detailed examination of the following concepts used in drug design such as: homologous series, isosteres, ring transformations, conformational restriction, homo- and hetero-dimer ligands
Quantitative Structure Activity Relationships: – the next step in structure activity relationship evaluation through the generation of linear regression modules to explore multi-parameter optimisation of compounds. For example the optimisation of compounds based on biological affinity, metabolic stability, solubility, permeability and other such physicochemical parameters.
Spatial Organisation, Receptor Mapping and Molecular Modelling: In these areas we extend learning and examine how molecules bind to their target proteins through exploring ligand-active site interactions. We begin to explore key concepts in designing new molecules to enhance key interactions leading to more affine compounds. We utilise state-of-the-art molecular docking techniques to design compounds and visualise how these molecules might bind at the molecular level to the active site of protein targets.
Patent evaluation: We examine what information is contained within a chemical patent and examine how we can use this information to generate potential fast-follower projects.
Team-based medicinal chemistry project: Working in the anti-malarial area, we investigate the mechanism of action of key anti-malarial compounds and design our own drug discovery programme presenting project ideas to a dragon’s den of experts.
Case Histories: We finally put our learning to practice through investigating case histories of successful drugs:
- Development of a Tyrosine Kinase Receptor inhibitor: Gefitinib
- Therapies for Hyperacidity: Development of proton pump inhibitors
- Design of the Anti-HIV Protease Inhibitor Darunavir
Drug Discovery and Development 2
The journey through preclinical drug discovery through to Investigational New Drug, clinical trials and launch. The focus is on understanding the relationship between drug blood/plasma concentrations and efficacy through the study of pharmacokinetics and drug metabolism. To facilitate that, there are several subthemes:
- The key organs in the body influencing drug pharmacokinetics
- The influence of pharmacokinetics in the drug discovery process
- In-vitro and in-vivo methods available for quantitative pharmacokinetics
- Compartmental and non-compartmental approaches to estimating pharmacokinetic parameters
- The prediction of human pharmacokinetic parameters and simulation of plasma concentration- time profiles
- The role of the Regulatory Authorities in drug development
Teaching on this module is delivered through a mix of lectures and workshops, with particular contributions from external speakers.
Drug discovery is a practical topic. This module provides an experience of contemporary drug discovery. Alongside the practical elements, the research project report will enhance transferable skills such as literature surveying, database mining, critical analysis and problem-solving.