Challenges and Opportunities
4.4 MODERN TRENDS IN DRUG DISCOVERY
4.4.6 Polypharmacological Profiling: A Novel Approach to Drug Discovery
Polypharmacology is a term that is used to describe compounds that interact with multiple targets. A recurring issue in drug discovery is drug
compounds acting on multiple targets; this has been termed as being “blind”
to other connected processes. The high throughput screening, computations structure-based approaches have evolved around the single-target approach.
Drug compounds acting on other targets have been attributed to adverse effects. There is an increasing paradigm shift from one-drug-target to one- drug-multiple-targets drug design. Instead of focusing on a single target, the newer strategies are evaluating varied levels of polypharmacology to identify the enhancing or undesired effects, and to determine its activity with antitargets [40]. Polypharmacological analysis of multiple targets (i.e., preferred macromolecules with which the drug is intended to interact) is important in drug development as it allows a more precise prediction of all the on- and off-target effects in order to determine the potential adverse effects of an intervention (Figure 4.3). Engagement of multiple targets by a drug molecule could be either beneficial (for repurposed drugs) or harmful (toxic). Certain drugs do possess multitargeting activities.
Aspirin is an analgesic drug popularly known for its pain relieving or fever reduction activity. However, it also acts as an anti-inflammatory med- ication to treat rheumatoid arthritis [41], pericarditis [42], and Kawasaki disease [43]. Additionally, it has been used in the prevention of transient ischemic attacks [44], strokes, heart attacks [45], pregnancy loss [46], and even cancer [47]. The rapid increase in molecular data generated in the postgenomic era has inspired a greater need for polypharmacological re- search to be fully incorporated in drug discovery. The omics technologies are also being incorporated [48,49]. Polypharmacology represents a gate- way to the rational design of the next generation of less toxic therapeutic agents to improve their effectiveness [50]. In addition, polypharmacological approaches are beneficial in the discovery of unknown off-targets for the existing drugs (also known as drug repurposing) [51]. Polypharmacologi- cal studies also require systematic integration of the multidisciplinary data from computational modeling, synthetic chemistry, in vitro/in vivo phar- macological testing, and clinical studies. Computational identification of combinations of drug targets has been a helpful way of selecting the most viable drug target [52].
Polypharmacological approaches help to increase the efficiency of drug action when developed with individual molecules that hit a useful set of multiple targets [6,7,53]. A single drug can act on multiple targets of a single disease pathway, or multiple targets associated with multiple disease pathways. For complex diseases, multiple drugs could act on different targets of a network to regulate various physiological/pathological processes [54].
Social Aspects of Drug Discovery, Development and Commercialization 100
The systems biology approach – investigating the drug–target interac- tions in the context of a molecular network – helps to deduce the poly- pharmacological relations among drugs and proteins [55–58]. Thus, systems biology approaches that are integrated with polypharmacology are being frequently used to identify new off-targets [59–61]. The polypharmacologi- cal phenomenon represents an important advancement in drug discovery as it enables the development of multitarget therapeutics agents to maintain an optimal balance of drug activity while uncovering the new off-targets and side effects for drugs: an emerging paradigm with a potential of transform- ing our next-generation pool of marketed drugs [62].
Polypharmacology has enabled the prediction of the activity of 656 marketed drugs on 73 unintended side effect targets, with confirmations on about half these predictions [63].
A polypharmacology approach allowed the identification of proteins linked by drug–target binary associations from a list of the US Food and Drug Administration-approved drugs. Moreover, polypharmacology has been credited for its speed and extensive capabilities in the identification of drug targets, which also opens up avenues to repurpose the existing drugs.
The use of “cocktails,” in other words multiple or single-drug molecules that engage different targets, has been employed in disease therapy such as HIV. For example, antiretroviral triple cocktail therapies for AIDS control can simultaneously suppress HIV fusion, while interfering with viral protein translation and transcription by using an HIV fusion inhibitor, a protease inhibitor, and a reverse transcriptase inhibitor, thus conferring resistance and preventing its maturity. This is a mechanism for minimizing a patient’s viral load down to almost basal levels and restoring white and red blood cells to- ward normal levels [64]. Until today, numerous polypharmacology-related problems do exist especially in modeling and rational design of multitarget- ing agents, which is highly cumbersome to accomplish.
4.4.6.1 The Road Ahead for Polypharmacology
A major advantage offered by the early application of polypharmacology is that it facilitates early decision making. Early decisions proactively address downstream complications, which stand to save financial losses and time.
The ICH regulatory guidelines, ICH S7A guidelines require “secondary PD studies” to investigate the effects of a substance not related to its de- sired therapeutic target. Polypharmacology belongs under this category and this study is undertaken to inform the selection and design of safe drug compounds and for its application in the interpretation of in vivo safety
pharmacology and toxicology studies. Understanding of the pharmacologi- cal safety properties of a drug could help the pharmaceutical company to outcompete the existing therapies for a disease, while offering advantage over its competitors and, most importantly, the promise of overall safety to the patients.
In an effort to strengthen the polypharmacology in drug discovery, academic–industry collaborations are been undertaken, which could elevate progressive research into potential adverse effects or drug toxicity in drug dis- covery. The NIH-based National Clinical Assessment and Treatment Service has launched programs to identify new uses for existing agents developed by the pharmas [65]. Ultimately, there is a growing expectation that sophisticat- ed and comprehensive polypharmacological approaches will emerge to fine tune the rational design of more potent and less toxic multitargeting agents to address the current experimental limitations and complexity.