From Target to Therapy: A Comprehensive Overview of the Drug Discovery Workflow

The path from an initial scientific hypothesis to an approved drug is long and fraught with challenges. On average, it takes more than 10 years and costs upwards of $2.5 billion to bring a drug from conception to market (DiMasi et al., 2016). Despite significant advancements in fields like computational biology and high-throughput screening (HTS), the attrition rate remains high, especially during clinical testing. Understanding each stage of the drug discovery process—from the initial identification of a therapeutic target through to clinical trials—is essential for medicinal chemists and researchers working to design effective, safe, and commercially viable drugs.

This article provides a detailed look into each phase of the drug discovery process, with a particular focus on the contributions of medicinal chemistry in optimizing lead compounds for clinical success.

• Genomic and Transcriptomic Technologies: Genome-wide association studies (GWAS) and RNA sequencing are often used to uncover genes or pathways associated with disease (Visscher et al., 2017). These methods provide insights into the genetic basis of diseases, highlighting potential targets for intervention.
• Proteomics: This technology helps identify proteins that are upregulated or altered in disease states, enabling the discovery of potential drug targets (Aebersold & Mann, 2016).
• Phenotypic Screening: In this approach, researchers use cellular or animal models to identify small molecules that produce beneficial biological effects, which can later be linked to specific molecular targets (Vincent et al., 2022).

The challenge in target identification lies in ensuring that the chosen target is both druggable and selectively modulated by small molecules, as these characteristics are essential for therapeutic intervention.

Once a potential target has been identified, the next step is to validate its role in the disease. This phase is crucial, as it confirms that modulating the target will yield the desired therapeutic effect.

• Genetic Validation: Tools like CRISPR/Cas9 or RNA interference can knock down or knockout genes of interest in cellular or animal models, providing direct evidence of their involvement in disease processes (Moore, 2015).
• Pharmacological Validation: Small molecules, biologics, or chemical probes can be used to modulate the target’s activity. If inhibition or activation of the target produces a measurable therapeutic effect in preclinical models, this strengthens its case for progression (Swinney & Anthony, 2011).

A validated target must demonstrate clear disease association, a well-defined mechanism of action, and the potential for selective pharmacological intervention without off-target effects (Emmerich, et al 2021).

Once a target has been validated, the next step is hit identification. This phase involves discovering compounds that bind to the target and modulate its activity. The most common method for hit identification is high-throughput screening (HTS), where large libraries of compounds are tested in automated assays designed to measure biological activity.

HTS is typically employed to test thousands to millions of compounds in a relatively short period. The process requires the development of robust assays that can detect the modulation of target activity with high sensitivity and reproducibility. Although the hit rate in HTS is generally low, identifying even a few promising compounds from a large library can provide a starting point for further development (Macarron, et al. 2011).

• Structure-Activity Relationship (SAR) Studies: Researchers synthesize and test new analogs of the hit compounds to understand how structural modifications impact biological activity.
• Pharmacokinetic and Toxicity Studies: Early assessments of absorption, distribution, metabolism, and excretion (ADME) profiles, as well as toxicity testing, are crucial to ensure that the compound is safe and effective in vivo.
• Optimization for Drug-Like Properties: Modifications to improve solubility, stability, and permeability are made, ensuring the compound’s bioavailability and reduced off-target effects.

The goal during this phase is to fine-tune the lead compound for further optimization while ensuring it has the desired characteristics necessary for preclinical development (Campbell, et al. 2018).

Lead optimization is a critical phase in the drug discovery process, as it involves refining lead compounds to improve their efficacy, safety, and pharmacokinetics, making them suitable for preclinical testing and eventual clinical trials.

• Stereochemical Modifications: Modifying the compound’s stereochemistry can lead to improved potency or selectivity.
• Scaffold Hopping: This strategy involves replacing the core structure of a compound with a different scaffold while maintaining target engagement. It helps overcome issues such as poor solubility or undesirable off-target effects (Hu et al, 2017).
• Pharmacokinetic Optimization: Strategies include altering lipophilicity or designing prodrugs to enhance bioavailability, reduce toxicity and improve stability towards metabolic enzymes (e.g. CYP)  (Ballard, et al. 2013).

At this stage, medicinal chemistry techniques are combined with pharmacological studies to create compounds with ideal therapeutic properties, ready for preclinical testing.

Before a drug candidate can be tested in humans, it must undergo extensive preclinical testing to evaluate its safety, efficacy, and pharmacokinetic properties. Preclinical development typically involves animal models, where the drug is tested for its therapeutic potential, safety profile, and ability to reach the target tissue.

• Toxicology Studies: These studies assess acute and chronic toxicity, as well as the potential for carcinogenicity, genotoxicity, and reproductive toxicity.
• Pharmacokinetic Studies: The drug’s absorption, distribution, metabolism, and excretion (ADME) profile are assessed again to ensure it behaves as expected in vivo.
• Formulation Development: Researchers design a formulation that can deliver the drug to the intended site of action effectively while ensuring stability and bioavailability.

Once preclinical testing is successful, an Investigational New Drug (IND) application is submitted to regulatory agencies like the FDA or EMA, requesting approval to begin clinical trials (FDA, 2020).

Clinical trials represent the final phase in the drug development process, where the drug candidate is tested in human subjects to assess its safety, efficacy, and overall risk-benefit profile. Clinical trials are conducted in three phases, each designed to answer specific questions about the drug.

• Phase I: This phase focuses on assessing safety, pharmacokinetics, and dosage in a small group of healthy volunteers.
• Phase II: A larger group of patients is treated to evaluate the drug’s efficacy and determine the optimal dose.
• Phase III: The drug is tested in a large cohort of patients (often thousands) to confirm efficacy and monitor long-term safety.

If Phase III trials are successful, the drug sponsor submits a New Drug Application (NDA) to regulatory agencies for approval.

The drug discovery process is a complex, interdisciplinary journey that requires collaboration among researchers from various fields, including biology, chemistry, and pharmacology. While the path from target identification to clinical approval is long and filled with challenges, advances in technology and methodology continue to improve the efficiency and success rates of drug development. Medicinal chemists, with their deep expertise in designing and optimizing small molecules, play a pivotal role in bringing promising drug candidates to the clinic. As the pharmaceutical industry continues to evolve, the integration of new tools and approaches will likely shorten timelines, reduce costs, and increase the probability of success, ultimately leading to the development of more effective therapies for patients.

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