In contrast to combination and single drug/single target strategies, polypharmacology (not to be confused with polypharmacy) suggests it is often desirable to develop single drugs with multiple therapeutic targets, although a handful of researchers use the term interchangeably with the use of drug cocktails. This paradigm shows immense promise in treating polygenic disorders as well as infectious diseases. Since the former involves networks of dysfunctional genes, and the latter, quite complex in its own right, is further complicated by drug resistance, it should be clear concentrating on one factor can yield less than stupendous results.
In the treatment of inflammation (Aspirin), psychiatric disorders (SSRIs), and cancer (Imatinib), it seems some of the most successful drugs attack several parts of a problem. Others have already been approved by the FDA and are simply waiting to be repurposed. Sildenafil, better known as Viagra, was originally meant to treat hypertension. Fate had other plans. As research progresses, and it most certainly will, it may be determined that these sorts of compounds are generally superior to their more selective counterparts. A major concern is that promiscuous compound has a higher chance of having unwanted side effects, yet when addressing multi-factorial problems this liability can be an asset. Cosalane, for instance, affects several HIV-1 enzymes. Because using multiple drugs is associated with higher risks of toxicity, antivirals that target HIV-1 while preventing opportunistic infections are sought after. Minocycline, a broad-spectrum antibiotic, inhibited HIV-1 integrase in vitro. Surely there are others like it on the horizon.
Cottarel et. al have suggested the development of antibiotic resistance is slowed considerably when multiple antibiotics are given simultaneously. Unfortunately, in a clinical setting, where patient compliance is absolutely necessary, this is not always feasible. Particular populations are less likely to adhere to their regimens than others. For this reason polypharmacological molecules are being investigated in the treatment of chlamydia. Using β-lactamase inhibitors with β-lactam antibiotics is done regularly to kill resistant strains. 15% of all trials conducted in the US in 2016 were for drug combinations. It is being broadly recognized that either combinations, or single multi-faceted molecules, are needed. Writing in 2014, Anighoro notes that of the papers on polypharmacology “100 were published in the last two years and more than 60 [in 2013].”
Jenwitheesuk et. al described a “novel paradigm” for drug discovery in 2008. In contrast to traditional docking (predicting how two molecules will fit together), the software he and his team designed is dynamic—in other words, much more true to life. Instead of using crystallized proteins in a single configuration, his program simulates numerous possible configurations under different conditions. They demonstrated the efficacy of their approach by screening 2,344 drugs and drug-like compounds against 16 proteins of P. falciparum, the parasite responsible for malaria. The 16 most promising molecules were tested further. Six had effects on the 3d7 and k1 strains. Previous attempts to develop new weapons against malaria using single-target thinking have not been successful. Only one of the 355,000 compounds screened in this way was deemed worthy of further investigation.
Adverse effects can be reduced by using a library of compounds with known toxicity profiles. Eventually screening, modifications to the molecules using the rules of medicinal chemistry, and toxicity assays, will all be done computationally. Donepezil, an ACE inhibitor used to treat Alzheimer’s, was modified it to add dopaminergic action to its function while improving blood-brain-barrier permeability and reducing the risk of dangerously low blood pressure. Similarly, ladostigil is used for a number of neurodegenerative disorders because it modulates an array of neurotransmitters. Polypharmacology should not veer into dangerous promiscuity and tissue types must always be taken into account. HER2 inhibitors, used to treat metastatic breast cancer, can be toxic to cardiac tissue.
Kinases, now marketed as cancer therapies, were once thought to be highly specific. It is now known many of them are “notoriously promiscuous.” Between 2001 and 2010 nearly 10,000 kinase inhibtor patents were filed in the United States. Kinases add phosphate groups to proteins. Needless to say, they are crucial for cell survival and proliferation. Unfortunately, as Knight notes, for types of cancer with the highest morality rates, colorectal, lung, pancreatic, breast, and prostate, kinase inhibitors have not been especially successful. Oncologists also encounter drug-resistant cells. In a trial with imatinib 90% of patients responded well, but 10% soon presented researchers with leukemic cells that blocked the proper binding of imatinib through a BCR–ABL mutation. In response to this, dastatinib and nilotinib were developed to overcome this bottleneck. The cancer kinome warrants an article of its own, so let us conclude here.
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