In focus: Unlocking the potential of GPCR targets

GPCR representation, the tertiary structure of bovine rhodopsin within the cell membrane (in grey). Source: Wikimedia Commons

PharmEnable has recently partnered with Sosei Heptares to work on a challenging G protein-coupled receptor (GPCR) target for a neurology disease indication. In the UK as of 2019, it is estimated that at least 1 in 6 people suffer from conditions of the central nervous system (CNS) [1], and in many cases there are still no effective treatments [2].

A common misconception is that GPCRs are easy targets for drug discovery. However, despite decades of research, the majority of the more than 400 clinically relevant GPCRs have yet to be drugged. These types of targets are commonly referred to as being “challenging” or “undruggable” [3].

Our CEO, Dr Hannah Sore said “GPCRs are very interesting targets that have been associated with a wide range of human diseases. These receptors are involved in key signalling pathways and have an enormous potential for the development of new drugs. Our partnership with Sosei Heptares will combine our key strengths to unlock this challenging target, bringing much needed benefit to patients.”


Why are GPCRs such interesting targets for drug discovery?

GPCRs represent the largest and most diverse group of receptors in humans with over 800 different receptors. Historically, these receptors have been a rich source of drug molecules, with more than 300 marketed drugs targeting around 100 GRCRs, representing ~25-30% of the therapeutically relevant family members [4].


Despite being the biggest family of membrane receptors in the human genome, with more than 400 receptors predicted to be therapeutically relevant, only <30% of GPCRs are currently targeted by drugs. Figures: A) From ~400 clinically relevant GPCRs, only 107 are currently established drug targets (with a drug in the market), 67 have reached clinical trials, and more than half have not yet been drugged. B) Disease area distribution for approved drugs targeting GPCRs. C) Distribution of GPCRs currently targeted by drugs. All figures generated with data from 

These receptors are embedded in the cell membrane and form extracellular vestibules that bind to a range of signalling molecules, such as hormones, growth factors and neurotransmitters. When a molecule binds to a given GPCR, a change in the tertiary structure occurs, and the transmembrane receptor adopts a slightly different shape, altering the way it interacts with intracellular components, called G proteins. It is the function of these G proteins to initiate and coordinate a wide range of cellular responses.

GPCRs control the crosstalk of many critical pathways between cells and organs regulating a broad range of cellular processes, from cell proliferation to signal transduction between neurons. Under normal conditions, these signalling pathways are tightly regulated, both temporally and spatially, and can work in concert with one or more processes or pathways to maintain optimal cellular function and health [5].

Disruption of the normal function of GPCRs can lead to the manifestation of disease, such as asthma, diabetes, obesity, gastrointestinal and neurological disorders [6]. Additionally, mutations in GPCRs are implicated in the development or progression of certain cancers [7]. This makes GPCRs an attractive set of targets to tackle difficult to treat diseases.


GPCRs and diseases of the central nervous system

GPCRs have been associated with the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and multiple sclerosis. Around 90% of the therapeutically relevant GPCRs have been found to be expressed in the human brain, and they play important roles in regulating mood, appetite, pain, vision, immune responses, cognition, and synaptic transmissions [8].

As such, modulation of GPCR function is expected to have great potential in the amelioration of these devastating diseases, but it is not without its challenges. CNS focused drug discovery is particularly challenging, as molecules are required to cross a natural defensive barrier that protects the brain from exogenous agents, called the blood-brain-barrier.

Dr Natalia Mateu, CSO said “During the last few decades, GPCRs have gained particular interest in the field of neurology for their role in the CNS. However, from a pharmacological point of view, they can be particularly difficult to drug with small molecules, especially within the CNS area, due to challenges of developing compounds with desired neurological drug-like properties.”

Representation of the blood-brain-barrier (BBB) – A blood vessel in the brain surrounded by astrocytes that make up the BBB. Source: modified from original (CC by 3.0).


A remarkable challenge

A highly valuable technique within the drug discovery toolbox is the use of structure-guided methodologies (called structure-based drug discovery, or SBDD). Drug hunters can use the structure of a biological target to design better molecules, whilst balancing overall drug-likeness. However, since GPCR proteins are complex and diverse in nature, the structural characterisation required for SBDD can be difficult to obtain for a variety of reasons.

GPCRs are large in size and have flexible regions both on the extracellular and intercellular membrane. These regions can vary widely between different members of the GPCR family, and they also reside in a dynamic and constantly moving cell membrane. This all adds to the intricacy when attempting to stabilise, isolate, purify and crystallise GPCRs to elucidate their protein structure. Additionally, this is further complicated by the uncertainty around protein dynamics and conformational diversity of the receptors’ tertiary structures, as well as post-translational modifications, which are critical for GPCR function [9].

An additional layer of complexity in drugging GPCRs comes in the form of selectivity. GPCRs are made up of various subfamilies that regulate different signalling pathways and biological processes. Many of the subfamilies have overlapping ligand binding sites, which means the protein sequences between different GPCR binding sites are very similar [10]. For example, some CNS drugs interact with more than one receptor. While that can be advantageous for their efficacy, poly-pharmacology can also lead to unacceptable side effects, limiting the use of some drugs. Again, structural information can be hugely powerful in designing new molecules with optimal selectivity profiles for a given target.

The task of developing new drug molecules is a costly and resource intensive process with high attrition rates in the clinic [11]. For challenging targets, obtaining structural information can help facilitate drug discovery efforts by providing novel insights into drug-receptor binding. These insights can help overcome issues related to selectivity allowing for development of safer medicines.

Our Director of Drug Discovery, Dr James Dale, said “When we evaluated this project, we first considered the impact to patients, particularly for those with neurological disorders. We then assessed the challenges around the target, with Sosei Heptares bringing novel structural insights on the target.” 

Our solution to a legacy issue

Given the history of GPCR drug discovery, many screening collections, which are used to identify chemical starting points for medicinal chemistry projects, contain molecules that modulate the function of GPCRs. However, there are still large gaps in our scientific knowledge of the function that some GPCR receptors play in human biology, and identifying the correct chemical matter to drug these targets is not trivial. Therefore, access to the right chemical matter is critical.

With traditional screening approaches, there is an inherent bias towards known biological target space, as screening collections are built from previous drug discovery efforts on different targets. Therefore, when screening against a novel target, any hit molecule will likely also be active against one or more other biological targets. These off-target effects can make the task of delivering a selective, and therefore safe, drug candidate all the more challenging.

One way to address this is to screen large collections of novel molecules, either via focused synthesis enrichment of physical libraries or virtually using computational methods. The problem with this approach is that the total available drug-like chemical space is astronomical in size and is estimated to be around 10^62 molecules. No screening collection, either physical or virtual, can ever hope to sample this space effectively.

Our unique approach in tackling this problem uses state-of-art artificial intelligence and machine learning with advanced medicinal chemistry expertise to map chemical space for a given biological target, identifying underexplored regions and populating them with novel 3-dimensional and complex molecules. In doing so, we enable the precise design of potential drug candidates with increased selectivity and improved drug-like properties.

Our Director of Technology, Dr David Vidal said: “At PharmEnable, we believe that the molecular entities that will unlock these challenging targets will be found in the yet to be explored regions of chemical space. With our partnership with Sosei Heptares, we have the opportunity to apply our hybrid human/AI-based platform to explore new areas of chemical space for this challenging GPCR target.”

A powerful combination

The partnership between Sosei Heptares and PharmEnable is highly complementary. PharmEnable brings the power of combining AI-enabled drug discovery with human expertise to deliver innovative small molecule drugs against challenging biological targets. Sosei Heptares has extensive knowledge around the GPCR target, as well as technologies and skills that can elucidate the structure of challenging GPCRs. By working together and combining our strengths we believe we can be more efficient at identifying new candidate drugs against this challenging target and provide much needed therapeutic benefit to patients.

Dr Jelena Aleksic, CBO, concludes: “We are very excited to be working with Sosei Heptares on this target. Together, we are aiming to deliver selective candidate molecules, with desirable neurological drug-like properties, to advance into preclinical studies. The project ultimately has the potential to have a significant impact on patients’ lives.”


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