2.1

Introduction

In the past decades, the predominant paradigm in drug discovery was the “one drug,

one target”, in which highly selective drugs were designed for individual targets.

This methodology was extremely successful for diseases with well-defined

mechanisms,

aetiology

and

pathophysiology

(Hopkins

and

Groom

2002;

Zambrowicz and Sands 2003). But a major pitfall of such a reductionist approach

of drug design was that one drug acts on a single receptor, “is blind” to other

processes which are inevitably connected in view of the hierarchical nature of

biological systems (Maggiora 2011). The mechanisms of some diseases such as

cancer are much more complicated as they stem from multiple genetic alterations,

and therefore, addressing a single target is usually insufficient to cure or contain such

diseases. Treatment of cancer with as single kinase inhibitor has been shown to be

insufficient in case of cancers of lung, breast, colorectal, pancreatic and prostate

(Yang et al. 2017). Therefore, the development of drugs that targets multiple proteins

or pathways holds more promise in the treatment of multi-target complex diseases.

The approval rate of new drugs has been decreasing in the recent times, and some

marketed drugs had to be withdrawn due to their unexpected side effects (Connolly

et al. 1997; Rothman et al. 2000). An interaction with unintended targets is one of the

main reasons behind drug side effects and toxicities. For instance, terfenadine, an H1

receptor antagonist, launched in 1982, was later withdrawn from the market as it

caused a life-threatening ventricular tachyarrhythmia, torsades de pointes, due to its

interaction with human ERG causing its blockage (Du-Cuny et al. 2011). Therefore,

identification of possible off-targets of drugs during early stages of drug discovery

may go a long way to prevent costly failures, since drug discovery is a complex,

time-consuming and expensive process.

Numerous drugs are known for their multi-targeting activities. An illustrative

example is aspirin that has been clinically used as an analgesic or antipyretic which

has been found to acts as an anti-inflammatory medication to treat rheumatoid

arthritis, pericarditis and Kawasaki diseases. Additionally, it has been also used in

the prevention of transient ischemic attacks, strokes, heart attacks, pregnancy loss

and even cancer (Reddy and Zhang 2013). In recent years, there is shift of drug

design paradigm towards polypharmacology, which is the ability of small molecules

to interact with multiple proteins. It is of much interest, as it has implications in

therapeutic efficacy, anticipating adverse reactions of drugs and to discover the

unknown off-targets for the existing drugs (also known as drug repurposing)

(Connolly et al. 1997; Reddy and Zhang 2013; Sahrawat and Chawla 2016). For

instance, the blockbuster drug sildenafil (Viagra), a phosphodiesterase (PDE) inhib-

itor, was initially developed for hypertension and ischemic heart disease. During

phase I clinical trials, its side effect of inducing penile erections was reported, and

after phase II clinical trial failure, sildenafil was repurposed for the treatment of

erectile dysfunction (DeBusk et al. 2004) and received FDA approval in 1998.

The concept of polypharmacology has been receiving unprecedented attention in

recent years. Using the keyword “polypharmacology” in a Google Scholar search

generated 8570 hits in the first week of April 2019 as compared to 3840 results as of

18

T. R. Sahrawat and R. C. Sobti