The journey from drug discovery to market is a complex and intricate process, often fraught with challenges and uncertainties. One of the most critical aspects of this journey is identifying and validating the targets of drug action. This article delves into the intricacies of drug targets, exploring questions of druggability, target validation, and the economic viability of drug development projects.
Early Beginnings: Observation to Hypothesis
In the early days, drugs were discovered through the observation of the effects of plants ingested by animals. This empirical approach, although still useful in some contexts, has largely been replaced by a more hypothesis-driven method. Modern drug discovery often starts with a statement or hypothesis that a specific protein or pathway plays a critical role in a disease. This leads to several crucial questions:
- Can a drug be found that will have the desired effect on its target?
- Will modulating the target protein affect the course of the disease?
- Is the project economically viable?
The answers to these questions often determine the effort and resources allocated to the drug discovery project.
Is the Target Druggable?
The concept of “druggability” refers to the likelihood that a drug can be developed to modulate a specific target effectively. Drugability is often determined by the presence of a binding site on the target that shows considerable affinity and selectivity for the drug. If the target is an enzyme or a receptor for a small ligand, the prospects are encouraging. However, if the target involves complex interactions between large peptides or proteins, the challenge becomes significantly greater.
Has the Target Been Validated?
Target validation is a critical step in drug discovery. Modern techniques in molecular biology offer powerful tools for this, especially when the biology of model systems closely resembles human biology. For instance, if disrupting a specific gene in a murine model shows beneficial effects for a human disease, it’s a strong indicator that the target is valid. Human mutations can also provide invaluable insights, as seen with the PCSK9 gene, which, when inhibited, lowers LDL cholesterol levels.
Target Validation: The Lesson of Leptin
The complexity of biological systems often poses challenges for drug discovery. For example, the hormone leptin, which suppresses appetite, initially seemed like an excellent target for treating obesity. However, further research revealed that obese individuals often have high levels of leptin but appear insensitive to its effects. This illustrates the importance of understanding the complexity and redundancy of biological systems when validating drug targets.
The economic aspect cannot be overlooked. The costs of drug discovery and development are astronomical, and a project that doesn’t make economic sense is unlikely to proceed, regardless of its scientific merit.
Identifying and validating drug targets is a complex but crucial component of drug discovery. It involves a multi-faceted approach that considers the druggability of the target, the validity of the scientific hypothesis, and the economic implications of the project. By paying close attention to these factors, we can improve the odds of bringing effective and economically viable drugs to market.
Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e Brunton LL, Hilal-Dandan R, Knollmann BC. Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.),Eds. Laurence L. Brunton, et al.