Harnessing Polypharmacology with Computer-Aided Drug Design and Systems Biology

Abstract

The ascent of polypharmacology in drug development has many implications for disease therapy, most notably in the efforts of drug discovery, drug repositioning, precision medicine and combination therapy. The single- target approach to drug development has encountered difficulties in predicting drugs that are both clinically efficacious and avoid toxicity. By contrast, polypharmacology offers the possibility of a controlled distribution of effects on a biological system. This review addresses possibilities and bottlenecks in the efficient computational application of polypharmacology. The two major areas we address are the discovery and prediction of multiple protein targets using the tools of computer-aided drug design, and the use of these protein targets in predicting therapeutic potential in the context of biological networks. The successful application of polypharmacology to systems biology and pharmacology has the potential to markedly accelerate the pace of development of novel therapies for multiple diseases, and has implications for the intellectual property landscape, likely requiring targeted changes in patent law.

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“…The identification of therapeutic need, coupled to sophisticated computational approaches, increasing News genetic and genomic information, exemplifies the value of a polypharmacological approach based on repurposing [4,5,7] and adds strength to the emphasis on precision oncology and personalized medicine [1,8]. As this report demonstrates, there is considerable value in examining existing drugs that have been approved or have at least passed through Phase I safety and tolerability studies as the path to clinical application is shortened considerably.…”

“…Finally, the work by Simbulan-Rosenthal et al [3] raises the awareness that compound libraries in pharmaceutical companies likely have a large number of "dormant" agents that possess multitarget activity but which were discarded due to 'off-target' effects in the quest for selectivity. The computational approach used in this and other studies by these investigators [4,5,7] may be a means of extracting valuable information from those libraries and adding new chapters to treatment approaches to oncology and other disorders.…”

Unexploited Antineoplastic Effects of Commercially Available Anti-Diabetic Drugs

“…Pleiotropy in biological systems is a long known phenomenon, commonly attributed to the complexity of intracellular signaling networks or tissue-specific cellular responses [ 1 , 2 , 3 , 4 ]. Consequently, a growing list of pharmacological agents is being reported to exhibit therapeutic potential in pathologic entities that are not mechanistically relevant with their current therapeutic use [ 5 , 6 , 7 ].…”

The purpose of repurposing

“…This study reaffirms the value of examining existing drugs such as mebendazole for potential clinical utility and for treatment options currently less than optimal. The identification of therapeutic need, coupled to sophisticated computational approaches, increasing genetic and genomic information, exemplifies the value of a polypharmacological approach based on repurposing [ 4 , 5 , 7 ] and adds strength to the emphasis on precision oncology and personalized medicine [ 1 , 8 ]. As this report demonstrates, there is considerable value in examining existing drugs that have been approved or have at least passed through Phase I safety and tolerability studies as the path to clinical application is shortened considerably.…”

“…Finally, the work by Simbulan-Rosenthal et al [ 3 ] raises the awareness that compound libraries in pharmaceutical companies likely have a large number of “dormant” agents that possess multitarget activity but which were discarded due to ‘off-target’ effects in the quest for selectivity. The computational approach used in this and other studies by these investigators [ 4 , 5 , 7 ] may be a means of extracting valuable information from those libraries and adding new chapters to treatment approaches to oncology and other disorders.…”