Polypharmacology – Foe or Friend?

Abstract

Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

“…Therefore, our data suggest that LDT3 and LDT5 are unlikely to cause the adverse effects associated with inhibition of important off-target receptors. We were also able to discard any interference of LDT3 and LDT5 (1 mM) with hERG K 1 channel function (data not shown), whose blockade can elicit potentially fatal cardiac arrhythmias (Priest et al, 2008), which is the reason why this test is absolutely required for new drug approval by regulatory authorities (Bowes et al, 2012;Peters 2013).…”

“…In the case of multifactorial diseases such as BPH (Roehrborn, 2008), a multi-target strategy seems more appropriate (Peters, 2013). For the treatment of BPH, the use of antagonists that concomitantly relax the prostate and slow prostate enlargement might be more effective than monotherapy targeting solely the a 1A -adrenoceptors (Hieble, 2011), so that we hypothesized that not only a 1D -adrenoceptors, but also 5-HT 1A receptors, could be additional targets.…”

Exploiting polypharmacology for drug target deconvolution

“…It is both a conundrum for the pharmaceutical industry and a tempting avenue for new approaches to drug development (17). Although industry has usually sought to develop drugs with high affinity and high specificity, there is acknowledgment that these two properties are not a prerequisite for either efficacy or safety.…”

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates

“…Key parameters that dictate successful SDD formulation include Log P, crystalline melting point (T m ), and the amorphous glass transition temperature for the drug substance. Molecules with moderate Log P values [2][3][4] and fewer hydrogen bond donating or accepting heteroatoms are generally preferred. The amorphous materials should have relatively high T g values (i.e., >40°C) for optimal physical stability to reduce the likelihood of crystallization.…”

“…More complex biological targets and modes of drug action, such as the recent focus on the benefits of allosteric modulation [1] and polypharmacology [2], have shifted molecular parameters [3] out of the traditional Brule of fiveĉ hemical space. Unsurprisingly, many drug candidates from this non-traditional space demonstrate poor physicochemical properties such as aqueous solubility [4,5].…”