A Journey Through the

Drug Discovery Pipeline

Written by

Laura Elizabeth Lansdowne

Sponsored by

T

he pharmaceutical industry primarily strives to bring new medicines to the market via a complex multi-step process that involves the “discovery” and “development” of a drug compound. Bringing a new drug from “bench to bedside” can take up to 15 years and is a costly endeavor – to develop a small molecule compound or biotherapeutic it is estimated to cost, on average, $2.6 billion. Before a drug is approved for use by the relevant regulatory authorities, it must go through rigorous testing to confirm its efficacy and safety, and several key considerations will be evaluated such as the most appropriate administration route for the drug, manufacturing suitability, cost-effectiveness and commercial viability.

In this article, we take a closer look at the various stages of drug development and highlight the instrumental role drug discovery plays in the process.


Click on the individual drug development steps to learn more.

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Key steps in drug discovery

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drug discovery project is typically initiated to address an unmet clinical need for an effective therapeutic for a particular indication. The process begins with initial or “basic” research, which is often conducted by academics. The primary goal at this stage is to identify a protein or pathway implicated in a disease or condition of interest, with the potential to be therapeutically targeted. It can take a number of years to gather enough supporting evidence before a target is selected for a drug discovery project – which is estimated to cost > $600 million. Once a target has been selected, focus shifts towards identifying molecules with suitable characteristics to make a drug. There are several subsequent steps involved and various approaches can be adopted.


Click on the individual drug discovery steps to find out more.

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1. Target identification and validation

Understanding the clinical spectrum of a disease and the role of a potential biological target in disease pathology is key to developing an efficacious drug. Targets come in various forms – receptors, enzymes, proteins, genes and RNA. For a target to be considered “druggable” its activity must be able to be modulated by a therapeutic agent. Certain targets are more amendable to small molecule discovery (e.g., G protein-coupled receptors) whereas others are modulated more effectively by biotherapeutics (e.g., protein antigen [target] and antibodies [biotherapeutic]).

Potential drug targets can be identified in different ways – by reviewing published literature, patent records and scouring open-access databases (data mining), or via experimental methods in the lab.

Broadly, target identification strategies can be split into two main categories: target deconvolution and target discovery (Figure 1). Target deconvolution involves the retrospective identification of a drug target in response to an observed (desirable) phenotypic response (from conducting phenotypic screening). Various techniques can be employed for target deconvolution including affinity chromatography, expression cloning, protein microarrays and biochemical suppression. Target discovery works on the premise that you want a drug compound and therefore a target must be identified to enable hit identification. The known target is then used to design relevant systems-based assays.

Figure 1: An overview of target identification and validation.


2. Hit identification and validation

Numerous screening approaches can be used to identify a “hit” compound. Hit is the term used to describe a compound that interacts with the target of interest. The output from these approaches provides the basis upon which drug design and elaboration are used to generate lead compounds with desirable properties.

High-throughput screening (HTS) involves the generation of a large library of compounds. These assays can be used to screen various library types (e.g., combinatorial chemistry, genomics, protein and peptide); thousands to millions of compounds are screened in parallel against a target. This screening approach is fast, cheap and relies heavily on automation. The success of HTS has been heavily influenced by advances in liquid-handing robots and miniaturization.

“The most fruitful basis for the discovery of a new drug is to start with an old drug,”

–  Sir James W. Black, recipient of the 1988 Nobel Prize in Physiology or Medicine.


Virtual screening
(VS) exploits computational approaches to “virtually screen” compounds to identify potential hits. Typically, large databases of commercially available compounds are virtually screened, however libraries of structures generated in silico from existing ligands can also be utilized to identify novel hits. VS can be a far more cost-effective approach to identify initial hits, as it circumvents the need to “physically screen” vast libraries against a biological target.

Fragment-based screening utilizes biophysical approaches to determine the binding of small “fragments” to a target. Initial fragment hits typically have a weak binding affinity to the target and associate with the target via “hot spots”. Fragment screening methods include NMR spectroscopy, SPR spectroscopy, X-ray crystallography, microscale thermophoresis, thermal shift assay and weak affinity chromatography. The initial fragments hits are subsequently expanded to produce larger molecules with higher binding affinity and are optimized to achieve a more desirable pharmacokinetic profile.

Identified hits are ranked and clustered according to their performance in several follow up experiments. Hits may be grouped based on structural similarity, to ensure various chemical classes are being considered. Dose-response curves are generated to compare potencies and in vitro assays are conducted to generate data on the absorption, distribution, metabolism and excretion (ADME) of the drug.

3. Hit-to-lead and lead optimization

Once the most promising hits have been confirmed, the next step is to refine them to produce compounds with higher potency and better selectivity. This step reduces the chance of off-target interactions which can lead to adverse effects. Medicinal chemists will work to increase the affinity of the compounds to the target of interest by several orders of magnitude. ADME properties are explored in more depth at this stage and the compounds are tested using in vivo disease models to determine pharmacokinetic profiles. Solubility and permeability assessments are carried out to determine the best route of administration and to eliminate compounds that lack the required properties to become a viable drug.

The goal of lead optimization is to retain advantageous properties previously defined, while optimizing the structure of each compound.


4. Candidate selection and preclinical testing

At this stage you will need to determine, from several promising leads, which one you want to take forward drug candidate for preclinical and clinical testing. Medicinal chemists will likely continue to produce “back up” molecules in case the lead selected for preclinical and clinical development fails. All the information gathered about the chosen molecule up until this point is used to construct a “target candidate profile” which is used as part of the investigational new drug (IND) application, for submission to the regulatory authorities.

Investigating Synthetic Immune Recruitment by Proximity Inducing Molecules

The recognition of cancer cells by the host’s immune system forms the basis of modern cancer immunotherapy. The development and validation of chemical tools that modulate the proximity of immune cells with cancer cells is essential for determining the mechanistic aspects of the recognition process and to aid immunotherapeutic design. Covalent immune recruiters (CIRS), one example of these chemical tools, function by forming selective irreversible linkages to both target antigens expressed on the cancer cell surface and natural immune machinery.

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