By Steven Fletcher
In 1906, Paul Ehrlich had a dream. He proposed the concept of a single drug to treat a disease with no side effects, which he referred to as “magische Kugel,” or in English a “magic bullet.” With regard to small molecules, then, Ehrlich imagined a drug that could selectively bind a single biological target responsible for the disease while simultaneously exhibiting “clean pharmacology.”
Making this dream a reality with small molecules has not been without its obstacles, but there are now several drugs available in the clinic. However, it is likely that many Food and Drug Administration-approved drugs developed through traditional drug discovery have varying degrees of activities at biological targets other than the intended target, but this is an acceptable flaw if side effects are minimal and/or beneficial to the patient.
For example, galantamine was developed as an acetylcholinesterase inhibitor to increase levels of acetylcholine and, thus, enhance activation of nicotinic receptors as an anti-Alzheimer agent. Curiously, galantamine appeared to possess greater efficacy than other inhibitors with similar affinities for the enzyme, and this has now been attributed to the drug also acting as a nicotinic positive modulator.
In contrast to Ehrlich’s magic bullet, it may be more desirable, and in some cases essential, to inhibit multiple biological targets to effectively treat a disease. Perhaps the most important and well-known example of targeting a single disease state with multiple drugs is HIV/AIDS therapy, wherein a patient typically takes a cocktail of three drugs that include reverse transcriptase inhibitors, protease inhibitors, entry/fusion inhibitors, and integrase inhibitors; there is no single HIV/ AIDS drug that is an effective treatment. Instead, multiple HIV targets and binding sites need to be simultaneously blocked to avoid the virus becoming resistant to a single drug due to its ability to rapidly mutate.
A drawback of treating a disease with multiple drugs is that each and every drug molecule has to successfully navigate toxicity and safety evaluations, and clinical trials would need to be conducted on the proposed cocktail regimen to rule out potentially harmful drug-drug interactions. Targeted polypharmacology, in which a single drug molecule is rationally designed to target multiple protein targets that contribute to the disease state, inherently circumvents the concern of drug-drug interactions.
The cover article in the July issue of the AAPS Newsmagazine explores polypharmacology as a complementary strategy with several advantages in the identification of efficacious therapeutics. Read Polypharmacology in Drug Design, from the DDDI section, and then participate in the discussion point below.
What do you see as the challenges to the development of drugs with polypharmacological profiles, from the computational chemistry all the way through to the regulatory science?