Introduction to Small Molecule Drug Discovery & Development

What does it take to advance a new drug from the laboratory bench to the patient’s bedside? Historically, drugs were discovered serendipitously and were usually isolated from natural sources. Today, drug discovery efforts take many years and cost hundreds of millions of dollars. They also require the input of dozens of specialists from a multitude of backgrounds to ensure that therapeutic molecules are efficacious and safe. This four-week course takes a high-level tour of what it takes to research and develop a new drug. We will meet different scientists and professionals across the drug discovery value chain as we explore the different stages of discovery and development, including the different tools and technologies that are influencing how we think about new medicines today. Starting off with the needs of the patient and the early phases of drug discovery, we will cover drug metabolism, pharmacokinetics and drug safety all the way to clinical development and beyond. This course is relevant for scientists who are new to drug discovery research or already have some experience, health professionals, or anyone who is interested in knowing what had to happen to ensure that their medicine is effective and safe.

• The starting point for drug discovery: The needs of the patient
• This week covers an introduction to the drug discovery and development process. It starts off by considering the patient, as the ultimate beneficiary of new and improved drugs, to ensure that they are kept at the centre of and integrated into all subsequent decision-making. Through a case study, the concept of an unmet medical need is introduced and provides a backdrop for understanding further critical concepts which underlie drug discovery and development. An overview of various drug discovery strategies is presented, along with approaches to screening and hit discovery. Various scientific, medical and humanitarian considerations need to be taken into account if effective delivery of new and improved drugs is to be achieved. Some of the challenges are presented, and a panel discussion highlights different, and similar, perspectives in the academic and industry approach to drug discovery projects.
• The early phases of drug discovery
• This week explores the early phases of drug discovery. As outlined previously, the starting point is always the needs of the patient and their biomedical realities. Understanding disease biology is a critical next step and sets the scene for mapping the context for immune response and the origins of ill health and how the progression of disease can be controlled or arrested. Case studies, particularly in the context of tuberculosis (TB), demonstrate the rationale behind molecular biology studies of the pathogen and the host. Key concepts such as the essentiality and vulnerability of targets and their 'druggability' are introduced. Medicinal chemistry drives the chemical modification of drug-like molecules to improve their activity and safety. The various tools and approaches that the medicinal chemist has at their disposal, including the value of the screening cascade, will be discussed.
• Drug metabolism, pharmacokinetics and drug safety
• This week picks up the drug discovery and development story at the point at which promising drug candidates have already been identified. The crucial importance in this phase of investigating the pharmacokinetics and pharmacodynamics of potential drugs is introduced, as these are key parameters for the effectiveness of a new drug and a positive patient experience. These properties have a bearing on bioavailability and metabolic processes and provide a backdrop for animal model studies, and the extent to which the biological properties of the drug are retained in mammalian systems. The ethical considerations and technological advances pertaining to in vivo testing are discussed. Drug testing, safety profiling, and toxicology and efficacy in preparation for clinical trials are presented, and an introduction to process optimization and API manufacturing is also discussed.
• Development phase
• This week outlines and examines the clinical development phase. Once a drug candidate has successfully progressed through the phases outlined previously, it qualifies for filing as an Investigational New Drug (IND) and a Clinical Trial Application (CTA) and the accompanying review process. An overview is given of the regulatory framework governing this, and a description of the various phases of clinical trials. The extensive teamwork that is required during the clinical trial is outlined, as well as the various role-players in this process, and some of the critical aspects, such as the submission and approval process, protocols that need to be established, informed consent and site management, are described. Finally, we look to the future and consider how new technologies are changing the face of drug discovery and development and how this may ultimately bring newer and safer medicines to the patient more rapidly.