Pharma’s Dirty Secret, And The Solution ahead: Polypharmacology

Recently I was undergoing acne treatment therapy when I faced the side-effects of drugs I was taking. I contacted the physician who was ignorant about them and said that these were normal. I researched a bit on these and noticed that almost all the drugs have side effects. The cold remedy makes us sleepy, sinus decongestant makes our heart race, and even aspirin can cause serious side effects. So the question arises:-

Why do drugs have Side-Effects?

There are mainly two things that complicate the ideal process. First, the body often uses the same chemical to regulate more than one function. This means that medicine might readjust one balance while disturbing others that would normally not need re-tuning. The drug prednisone, for example, turns off inflammation but also raises the blood levels of sugar and causes thinning of bones.

Secondly, medicines are not always as selective as we would want them to be. This means that the medicine also binds to many other receptors, causing side effects that can range from a harmless dry mouth to life-threatening reactions. For example, Imodium, a drug that treats diarrhea, can also cause abdominal pain, drowsiness, and dry mouth.

These multi-receptor drugs are so notorious, they are known informally in the pharmacology business as “dirty drugs,” and this interaction of drug molecules with multiple targets is coined as “polypharmacology.”

Polypharmacology: A new approach

As is often said about the creation of the universe, “The beginning is the end,” likewise in this context, “The problem is the solution.” Many of the dirty drugs on which we depend work precisely because they bind to so many different receptors, often different aspects of the condition being treated. If we lean into the multi-receptor approach by applying advanced biotechnology in the pursuit of polypharmacology — the design of drugs that act on multiple targets or disease pathways, then by which we can find not only drugs without unwanted side effects but also better candidates for treating highly complex, multi-target diseases like obesity and diabetes.

Due to the exponential growth of molecular data and fast advancement in technologies, the efforts of drug discovery have been tremendously amplified. The philosophy of drug design has been transformed from “one drug one target” to “one drug multiple targets.” Polypharmacology is emerging as the next paradigm of drug discovery. Polypharmacological phenomena include:-

• single drug acting on multiple targets of a unique disease pathway
• single drug acting on multiple targets pertaining to multiple disease pathways.

In addition, polypharmacology for complex diseases is likely to employ multiple drugs acting on distinct targets that are part of a network regulating various physiological responses. The Polypharmacological approaches aim to discover the unknown off-targets for the existing drugs (also known as drug repurposing). The approach needs the systematic integration of the data derived from different disciplines, including computational modeling, synthetic chemistry, in vitro/in vivo pharmacological testing, and clinical studies.

Patient Safety

However, polypharmacology has the potential to cause problems when it is not used correctly or insufficient information is known about the activity of the drug. This is primarily as a result of adverse effects that result from secondary drug targets.

For example, Lumiracoxib was removed from Australia’s drug market due to concerns of the non-steroidal anti-inflammatory drug acting on the liver and leading to hepatic failure. Other drugs that have been the subject of similar concerns in respect to polypharmacology include rofecoxib and staurosporine.

The safe and effective use of medications with polypharmacological properties requires extensive data collation to ensure the best results. This process included computer models, synthetic chemistry, pharmacological testing, and clinical trials before it can be implemented in widespread practice.

Challenges

Despite their evident growth, polypharmacological approaches are attributed to several challenges. The major limitation is that we only partially understand the pathways/mechanism of many diseases at the molecular levels. It is exceedingly difficult to derive the full polypharmacological networks without the complete data. Additionally, more accurate mining techniques and mapping methodologies are needed to analyze the complex data. On the other hand, understanding the convoluted associations is also a challenging task after the complex networks are constructed. Additionally, the costs to conduct necessary studies can be high.

Future of Drug development

Polypharmacology certainly has the potential to play a larger role in the development of drugs in the future. However, it is essential that appropriate care is taken to reap the benefits of multiple drug actions while minimizing the associated risks.

It is expected that in the near future, there will be more research in this area, particularly in the field of drug repurposing and extending the utility of drugs already approved for safety. This is likely to grow into the future, perhaps expanding to develop drugs initially to target unique pathways in the body.

References:

• Reddy AS, Zhang S. Polypharmacology: drug discovery for the future. Expert Rev Clin Pharmacol. 2013 Jan;6(1):41–7. DOI: 10.1586/ecp.12.74. PMID: 23272792; PMCID: PMC3809828.
• Interview of octant bio: Forbes