Understanding Basic Principles of Pharmaceutical Drug Discovery

June 10, 2021 - Drug discovery is a crucial part of the drug development pipeline, beginning with the identification of a disease target to the creation of lead compounds. According to Amanda Garner, PhD, Associate Professor in the Department of Medicinal Chemistry at the University of Michigan’s College of Pharmacy, a molecule is at the beginning of every drug development pipeline.

In a recent PharmaNewsIntelligence webcast, Garner spoke the role of discovery in pharmaceutical research, the evolution of discovery from disease to lead compounds, and key considerations associated with the discovery process. 

Drug Discovery  

A large part of contemporary drug discovery has been shaped by an increased understanding of the human genome led by the Human Genome Project, Garner noted.

The sequencing of the human genome was one of the major advances in science that brought with it the promise of drug targets for nearly every existing human disease. 

Humans have nearly 21,000 protein-coding genes, or about 21,000 potential drug targets. This finding drove the idea of targeted drug discovery where researchers could focus on specific targets and the idea of personalized medicine.

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At the beginning of every clinical type or drug discovery pipeline, there's always some molecule and numerous possibilities for different target types. Then, there is the breakdown mainly going after gene protein-couple receptors (GPCRs), nuclear receptors, ion channels, enzymes, transporters, kinases, and other types of targets.

At this point, researchers can shift their focus to a vast majority of the human proteome and find what the status is. A proteome is the complete set of proteins encoded by a particular genome. 

About three percent of a proteome is targeted by existing drugs. Looking specifically at targets that already have some kind of drug-like molecule, there is about a seven percent expansion into additional target classes.

Therefore, the bulk of discovery in terms of targets and small molecules is looking at these targets with an established biological relevance, as well as new approaches for translating basic science studies.

Basic science studies have driven new biological investigations. Researchers can further understand the vast majority of protein-coding genes and take advantage of this information for clinical applications. 

What Makes a Good Drug Target? 

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When researchers think about what makes a good drug target, they’re going to start with a disease with some high unmet medical need.

Gene association studies are a leading way that researchers identify a molecular drug target for a specific disease that they’re already interested in studying.

And thinking about modern technology, CRISPR allows researchers knock out any gene in a cell, and it is playing a crucial role in discovering the significance of potential targets in certain diseases. Over the past few years, it has become increasingly popular in medicine. 

This technology could lead to animal models, imaging studies, biomarkers of a disease, and targets that could lead to the production of that biomarker.

Biomarkers are an aspect of discovering a drug target because assessing the activity of the drug as it goes through the drug discovery and development pipeline is essential. Generally, a drug is much more likely to be approved if it has a valid biomarker. 

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According to Garner, identifying a molecular drug target is essentially allowing one to come up with a therapeutic hypothesis. In order to do so, there needs to be an experiment to test whether the hypothesis is valid, referred to as target validation. 

“It really is a major and significant process in drug discovery,” Garner stated. 

Another important step in defining a drug target is drug ability. 

Drug ability is how likely a biomolecule can be manipulated with an exogenous drug, and  researchers have access to many different modalities outside of small molecules. For example, peptide drugs bridge the divide between small molecules and biologics. 

Small molecules refer to traditional drug molecules, such as blockbuster drugs such as Lipitor, Eliquis, Savaldi, and Imbruvica. And biologics refers to an expanded range of therapies, including monoclonal antibodies and RNAs. 

RNAs recently gained approval a few years back for very rare diseases and are now being expanded into more mainstream diseases. mRNA has also been more well-known because of its presence in the FDA-approved COVID-19 vaccines. 

Garner stated that researchers will continue to leverage these platforms for the expansion of drug ability.

How Are New Medicines Discovered? 

The first step to drug discovery is finding a target and next step is finding the molecule that researchers are able to develop. New medicines are typically discovered by two main screening strategies: phenotypic screening and target-based screening.

Garner explained that phenotypic screening identifies compounds that can induce a phenotype change. This type of screening could go from gain of function to loss of function in the presence of a compound. With phenotype-based drug discovery, researchers would go from assay development, to directly screening for compounds, to identifying hits and leads.

Another method is target-based screening wherein researchers have a known and validated target that they want to identify compounds with based on a therapeutic hypothesis. 

In this case, there is already a starting target, whereas in phenotype-based drug discovery, a target is discovered. 

Garner highlighted some pros and cons for each type of screening. 

In phenotypic screening, the drug target is unknown, but the caveat to that is that there is going to be screening in cells and animals, which are more physiologically relevant to a disease. 

In target-based screening, researchers are screening against purified protein or cell lines that are overexpressing the target, so the assays that can be done have higher throughput, Garner explained.

This means researchers can screen many more compounds to find the ideal compound for the target. 

However, the downside to this type of screening is that researchers have to confirm that their compound can actually elicit an effect in a biological system. 

In drug discovery, there are many failures in late-stage clinical development. One of the main reasons for drug failure centers on drug efficacy of the drug. Efficacy becomes a major factor when thinking about targets in drugs that go beyond novel pathways. 

Early drugs were on the whole phenotypic-screening based, Garner explained. They may have been based on plant medicines or may have been accidentally discovered. But today, both phenotype screening and target-based screening have become driving forces, alone and together. It's not one or the other. 

Years ago, people may have doubted the ability to find a target for a compound. But now, with all the technologies that exist, good single target or small subset of targets are discovered more often than not.