Systems Pharmacology
Figure 2:Comparison of the classic v systems biology v systems pharmacology approach. a) Representation of the one drug-one target model. b) Representation of a systems biology perspective of therapeutic drug effects . c) Representation of the one drug-multi-target-pathway/network approach of systems pharmacology. Note that the figure was adapted and modified from the work of Mikel Elorriaga (
https://www.slideshare.net/mikeltxopiteaelorria/advanced- systems-biology-methods-in-drug-discovery)
24 (40%) of them were classified as ‘molecularly targeted’ representing a new annual record for precision medicine drugs approved31. This contin- ues the trend from 2017 where of the 46 new drugs approved 16 of them (~35%) were classified as precision medicine drugs2. The use of precision medicine drugs is another example being employed by the pharmaceutical sector to improve the quality of therapeutic drugs provided to indi- vidual patients. These advances are predicated on the advent of precision medicine and its focus on the grouping and identification of sub-populations (1-in-N model). In turn, precision medicine was conceptualised from our more refined and detailed understanding of human pathobiology and patho- physiology brought about by the development of
systems biology tools, technologies and insights17- 19,24,27.
Systems pharmacology The old model of ‘one drug-one target’ was devel- oped on the assumption that specific drug treat- ments would be superior due to the absence of off- target side-effects. However, the promiscuity of drugs that bind to numerous targets is now a well- characterised phenomenon20-22. Recently it was estimated that promiscuity rates varied from 6-28 individual targets per therapeutic drug21! It is noteworthy that armed with hindsight, most Blockbuster Drugs (one drug-one target) are pleiotrophic in nature. In other words the drug has
38
both numerous beneficial and adverse effects on the patient. A well-known example of such a drug is aspirin. The drug manifests effects in the treat- ment of inflammation, pain, fever, assorted can- cers, stroke and cardiovascular disease, but is also associated with gastritis and bleeding. Aspirin was recently reported to have an estimated 23 different putative targets, possibly explaining the pleiotrophic properties of the drug32. A 21st-cen- tury example of another widely-used pleiotrophic drug(s) is the statin family members. In both cases the one drug-one target model was used originally in the development of such therapies, without the insights of drug promiscuity.
Definitions The growing body of evidence from drug promiscu- ity and systems biology studies indicated that the ‘magic bullet’, one drug-one target model was sim- plistic. In part, this is due to the compensatory mechanisms and redundant functions present in biological systems, facilitating a resilience to single- target drug perturbations. Currently, it is under- stood that many drugs bind to multiple targets that in turn participate in, and are associated with, mul- tiple biological processes. This property is referred to as drug polypharmacology22. The term was applied originally to off-target adverse effects of the drug. More recently, the definition has morphed to reflect the exploitation of these characteristics in a more beneficial manner. Polypharmacology is now
Drug Discovery World Winter 2018/19
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68
