- Irritable bowel syndrome (IBS) affects around 1 in 10 people.
- Dr Stoyanka Nikolova from the University of Plovdiv, Bulgaria, has collaborated with fellow researchers to propose new drug candidates that could be used to treat conditions such as IBS.
- Using computer and laboratory techniques, the team has explored the effects of a hybrid drug candidate based on two different groups of medications.
- The results showed that hybrid molecules exhibited anti-inflammatory, antimicrobial, and antispasmodic effects, suggesting they are promising options for preclinical trials.
Irritable bowel syndrome (IBS) is one of the most common disorders of the gut-brain axis and is estimated to affect around 10% of people globally. IBS is a functional condition, meaning that treatment centres around managing symptoms and improving quality of life for those affected. There can be an increase in sensitivity to pain in patients with IBS, known as visceral hypersensitivity. Therefore, treatment options sometimes focus on managing pain pathways within the gut, as well as pathways that lead to symptoms such as abdominal spasms and cramps.
There are options to utilise existing knowledge about pathways to target for IBS symptoms, or to validate new drugs with novel mechanisms of action.
Multiple treatment options are available for IBS, including diet, lifestyle, and medication. The most common types of medication used for IBS are anti-diarrhoea medication, along with drugs that influence the activity of neurotransmitters and those that can manage symptoms such as painful bowel spasms, called antispasmodics.
Mebeverine is one such medication commonly used to help manage IBS symptoms. It reduces the contraction of smooth muscle cells, causing the gut muscles to become more relaxed. However, not everyone responds to the treatment in the same way, highlighting the need for new pharmacological strategies for IBS that can be used alongside diet and lifestyle changes.
Dr Stoyanka Nikolova from the University of Plovdiv, Bulgaria, explains that there are also options to utilise existing knowledge about pathways to target IBS symptoms, or to validate new drugs with novel mechanisms of action.
Identifying suitable candidates
For their research, Nikolova and team explored the potential of two different groups of medications, anthranilic acid derivatives and phenylethylamines. Drugs such as non-steroidal anti-inflammatory drugs (eg, diclofenac) are derived from anthranilic acids. This group of compounds is also known to have antiviral and antibacterial effects.
The researchers have considered phenylethylamines due to their ability to interact with serotonin receptors and to activate these receptors in the same manner as the serotonin neurotransmitter. Other medications that interact with serotonin receptors are often used in mood disorders, such as depression and anxiety, but are also part of the treatment pathways for IBS. They can act as antidepressants for the gut and are helpful given the link between the gut and the brain, as well as the presence of visceral sensitivity within the gut.
Exploring a new hybrid
Using computer techniques, the researchers hypothesised that a molecule that is a hybrid of these two types of medications may be a promising candidate for a new antispasmodic drug that would have the benefits for managing conditions such as IBS. The researchers investigated factors such as how the molecules might work within the body, what beneficial properties they could possibly have, and how stable they would be as a medication.
The research team used a variety of different scientific tools to assess the novel molecule and similar molecules which could potentially be drug candidates. They explain that to be successfully used as a drug, a molecule must reach its pharmacological target within the body and be present at the correct concentration when it arrives, before staying in its active form long enough to carry out its required function.
The project used computer modelling techniques to predict the molecular, biochemical, and physiological effects of the hybrid molecule. As the results of the computer studies looked promising, as a next step, the researchers synthesised the molecule so that it could be tested in the laboratory.
The molecules in action
Using cells grown in the laboratory, the team explored the antimicrobial, cytotoxic (ability to be toxic to cells), and anti-inflammatory properties of the new molecules compared to Mebeverine. The results showed that the hybrid molecule had more effective antimicrobial properties than Mebeverine in the same concentration range when tested against bacteria, yeasts and fungi. They also showed a better cytotoxicity profile, with a longer lasting pattern of activity.
There was also evidence of smooth muscle relaxation when the drug candidates were tested on tissue from rodent models, meaning that they could have good antispasmodic effects. Additionally, all the hybrid compounds that were tested were able to protect proteins against heat damage, suggesting they may have benefits for protecting cells and proteins from damage, which can be caused by inflammatory processes within the body.
The laboratory experiments and theoretical calculations showed that two of the new hybrid molecules may be interesting drug candidates.
Two of the newly synthesised hybrid molecules showed the most promising results as new pharmacological agents. They were able to form strong bonds within protein molecules which helped prevent damage, also suggesting that they may have good anti-inflammatory properties as there is also a risk of damage to proteins and other tissues during inflammation.
The hybrid compounds also interacted strongly with DNA, meaning that they may be able to prevent replication of damaged DNA, something that is important when considering drugs to combat tumour development, for instance.
The future of treatments?
Nikolova and colleagues report that the laboratory experiments and theoretical calculations showed that two of the new hybrid molecules may be interesting drug candidates.
Both hybrid molecules seem to include a combination of compounds they are based on: the anti-inflammatory properties of anthranilic acid and the antispasmodic properties of serotonin receptor agonists such as phenylethylamines. The researchers predict that they could be used to fight infectious diseases while emphasising that further preclinical studies are required to explore this potential.
What do you enjoy most about the field of drug discovery?
The search to find a new successful treatment for common diseases is one of the most intriguing aspects of the research for me. My motivation comes from both the curiosity to explore the current progress on therapies of significant pathologies, and the desire to make a difference in medicinal and bioorganic chemistry by overcoming the side effects of these therapies.
I can openly say that in our research team, everyone is a dreamer, and we truly believe we are on the right path of researching, planning, and synthesising a new, improved drug molecule that would treat not only the symptoms but also some of the most common reasons for IBS, such as chronic inflammation and bacterial infections. By selecting the proper pharmacophores, or the molecular fragments that contribute to the biological activity, we aim to design a molecule with high therapeutic and minimal adverse effects. This synthetic process is a chemical game of Lego, and we are trying to build the ‘highest and most stable tower’ from our ‘blocks’.
If you are not convinced that this is exciting, then imagine what it is like to collaborate with scientists from 3 to 5, or even more, highly specific fields and discuss with them possible experiments regularly – it is like touring different museums or galleries every day! We are able to look at the process of drug discovery from completely different viewpoints – what functional groups should the drug molecule have, what cell mechanisms should be targeted, what methods could be used to assess the biological effects, and why the experimental results make sense in terms of chemistry, biology, physics, pharmacy, and medicine.
It is very inspiring to know that the hours spent synthesising a compound could make a significant impact on humanity one day.
What would be the next steps in testing the hybrid molecules?
Our upcoming plans are to continue investigating the biological effects of hybrid molecules. We base all our experiments on pre-made computer software calculations which show a list of probabilities for the molecules to express certain therapeutic effects. We will then select, for synthesis and biological experiments, only the highest scoring compounds for our focus effects for IBS treatment – spasmolytic and anti-inflammatory. Now that we have confirmed these activities using different in vitro and ex vivo tests, we would like to broaden the information on the therapeutic potential of the most active hybrids.
We plan to investigate the antimicrobial properties in the context of bacteria-caused symptoms of gastrointestinal inflammation as well as the effect on blood coagulation, and on some central neural system functions like stress and memory. The last two might seem like a stretch, but they do make sense when we look at IBS as a prolonged, life-influencing condition causing other stress-related symptoms.
Our attention lately has also been drawn to improving the pharmacokinetics of the hybrid molecules, mostly concerning the comfort of patients who might be treated with them. We would like to ensure that the hybrids would be effective in oral treatment, and possibly prolong the time between two applications up to 12 (or even 24!) hours. We believe this would be possible by incorporating the hybrids in metal nanoparticles or as ligands in metal chelates. This is also expected to allow lower doses for treatment if combined with conventional methods for physical therapy.
Why is there an ongoing need for new medications to manage conditions such as IBS?
IBS is a common functional gastrointestinal disorder without a known biological cause. For example, in some people with IBS, food may move too slowly or too quickly through the digestive tract, causing changes in bowel movements. Unfortunately, there is no such thing as a ’magic pill’ or a highly selective drug that can treat IBS. Currently, many medications are used for the treatment of patients with IBS, but IBS management also relies on dietary and lifestyle modifications. Application of non-steroidal anti-inflammatory drugs to relieve pain and inflammation and to reduce IBS symptoms is also an option.
However, the side effects of currently available anti-inflammatory medications have limited their usage. Due to the adverse effects of these drugs, there is a high demand for the search for new drugs with fewer or no side effects. And that’s what we are doing – replying on a more focused interaction between basic scientists, pharmacologists, and clinicians to act toward not only the symptoms but the entire pathophysiological mechanism, therefore improving the overall treatment of IBS.
