Polypharmacology – a novel and rising concept in treatment of the diseases

Polypharmacology is the rising innovative concept that focuses on the multi-target drugs. This field is separated from the classical “one drug, one target” philosophy.

This concept has been gaining a growing attention since the 1990s.

Definition of Polypharmacology:

Polypharmacology is the treatment of diseases by modulating more than one target.

Polypharmacology

According to Andrew L. Hopkins from Department of Biological Chemistry and Drug Discovery, University of Dundee, UK, Polypharmacology can be defined as, “The modulation of several drug targets to achieve a desired therapeutic effect.”

Moreover, Aislyn and Ravi have presented that the “definition of polypharmacology encompasses both one drug binding to multiple targets and multiple drugs that bind to different targets within a network.”

Advantages of Polypharmacology:

It is an important area of integration between systems biology and drug discovery.

With the help of polypharmacology, researchers from different field can target complex diseases effectively such as the diseases with multiple pathogenic factors or diseases involving many genes.

Working on such drugs that have multiple targets could save a huge amount of money. It has been estimated that Research and Development efforts for a drug to move from the clinical trials to the market takes from 5 to 10 years and costs about US $1 billion. If the drug is for one target, it means the drug is effective for either one disease or a limited number of diseases but if the drug has a number of targets, it could effectively treat a number of diseases. So, the Pharmaceutical companies would be able to work against many diseases at the same cost and the consumers would be able to get single medicine for different (almost related) disorders. (It has been estimated that the value of many of the blockbuster drugs is about US $160 billion for generic manufacturers but the patents of those drugs will be expired by the next 3-5 years that would place the companies in a huge financial and research competition).

Products of polypharmacology have not only increased therapeutic potency but also they are less likely to the development of resistance. They can also help in the prediction of side-effects by identifying multiple protein targets. (Unacceptable side-effects usually cause one-third of the potential therapeutic compounds to fail either in the clinical trials or in the market even after its launch.)

Comparison of therapeutic and adverse polypharmacology (Credit: Curr Opin Drug Discov Devel.)
Comparison of therapeutic and adverse polypharmacology (Credit: Curr Opin Drug Discov Devel.)

Examples of products:

An example of the drug that works as a polypharmacologic product is “Memoquin”, which is a novel multi-target compound for Alzheimer’s disease. You can see more examples in the figure.

Examples of therapeutic polypharmacology (Credit: Curr Opin Drug Discov Devel.)
(A) Resistance to β-lactam antibiotics (eg, amoxicillin) is caused by degradation of the drugs by bacterial β-lactamase. Inhibitors of β-lactamase (eg, clavulanate) prevent the degradation of the antibiotics, thereby increasing the effectiveness of these drugs. (B) Notch mutations are associated with cancer. Several drugs have been designed that target γ-secretase, the enzyme upstream of Notch; however, resistance to these γ-secretase inhibitors (GSIs) can be caused by mutations in the MYC gene. A combination of drugs that target both Notch and Myc (through inhibition of CDK4) has been demonstrated to reverse Myc-induced GSI resistance and effectively treat cancer. (C) The anticancer agent sorafenib is an example of a drug with multiple targets (eg, Raf and PDGFR/VEGFR) that is used to treat a single disease (ie, renal or liver cancer). (Credit: Curr Opin Drug Discov Devel.)

Further Reading:

Aislyn DW Boran and Ravi Iyengar, (2010). Systems approaches to polypharmacology and drug discovery. Curr Opin Drug Discov Devel, 13(3): 297–309. PMCID: PMC3068535

Durrant, J., Amaro, R., Xie, L., Urbaniak, M., Ferguson, M., Haapalainen, A., Chen, Z., Di Guilmi, A., Wunder, F., Bourne, P., & McCammon, J. (2010). A Multidimensional Strategy to Detect Polypharmacological Targets in the Absence of Structural and Sequence Homology PLoS Computational Biology, 6 (1) DOI: 10.1371/journal.pcbi.1000648

Polypharmacology in Drug Discovery by Jens-Uwe Peters

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