Finding novel pharmaceuticals in the systems biology era using multiple effective drug targets, phenotypic screening and knowledge of transporters: where drug discovery went wrong and how to fix it

Abstract

Despite the sequencing of the human genome, the rate of innovative and successful drug discovery in the pharmaceutical industry has continued to decrease. Leaving aside regulatory matters, the fundamental and interlinked intellectual issues proposed to be largely responsible for this are: (a) the move from 'function-first' to 'target-first' methods of screening and drug discovery; (b) the belief that successful drugs should and do interact solely with single, individual targets, despite natural evolution's selection for biochemical networks that are robust to individual parameter changes; (c) an over-reliance on the rule-of-5 to constrain biophysical and chemical properties of drug libraries; (d) the general abandoning of natural products that do not obey the rule-of-5; (e) an incorrect belief that drugs diffuse passively into (and presumably out of) cells across the bilayers portions of membranes, according to their lipophilicity; (f) a widespread failure to recognize the overwhelmingly important role of proteinaceous transporters, as well as their expression profiles, in determining drug distribution in and between different tissues and individual patients; and (g) the general failure to use engineering principles to model biology in parallel with performing 'wet' experiments, such that 'what if?' experiments can be performed in silico to assess the likely success of any strategy. These facts/ideas are illustrated with a reasonably extensive literature review. Success in turning round drug discovery consequently requires: (a) decent systems biology models of human biochemical networks; (b) the use of these (iteratively with experiments) to model how drugs need to interact with multiple targets to have substantive effects on the phenotype; (c) the adoption of polypharmacology and/or cocktails of drugs as a desirable goal in itself; (d) the incorporation of drug transporters into systems biology models, en route to full and multiscale systems biology models that incorporate drug absorption, distribution, metabolism and excretion; (e) a return to 'function-first' or phenotypic screening; and (f) novel methods for inferring modes of action by measuring the properties on system variables at all levels of the 'omes. Such a strategy offers the opportunity of achieving a state where we can hope to predict biological processes and the effect of pharmaceutical agents upon them. Consequently, this should both lower attrition rates and raise the rates of discovery of effective drugs substantially.

What would be the observable consequences if phospholipid bilayer diffusion of drugs into cells is negligible?

“…The hypothesis-led approach is the one I have taken here, and the many publications analysed in our various papers on this topic (e.g., [5,6,[12][13][14][15][16][17]19]) provide data and evidence that, perhaps surprisingly, or even shockingly, thus far fail to falsify the hypothesis that, for the transport of pharmaceutical drugs across intact biological membranes, phospholipid bilayer diffusion is negligible. Many opportunities for novel approaches exist (Box 1), however, and I look forward to further tests of these consequences.…”

“…Of course, these transporters are taken to be there not specifically for the benefits of pharmaceuticals companies but for the purposes of intermediary metabolism. To this end we have summarised the evidence for the dominance of transporter-mediated uptake in several review and experimental articles [5,6,[12][13][14][15][16][17][18][19].…”

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

“…Direct effect by linking of anesthetics to proteins and indirect action on the lipid membrane properties are the two hypotheses in conflict’.” Counter: this is an example of highly selective reporting; the paper cited is not even about biological membranes, and the apodosis of the title of the paper (“looking for a lipid-mediated mechanism of anesthesia”) implies an agenda that seeks to pre-judge the answer. We have discussed the extensive literature of general anesthetics many times (Dobson and Kell, 2008; Dobson et al, 2009a,b; Kell and Dobson, 2009; Kell et al, 2011, 2013; Kell, 2013; Kell and Goodacre, 2014), and the available data show clearly the involvement of a variety of proteins such as GABA A receptors (Mihic et al, 1997; Jurd et al, 2003; Bonin and Orser, 2008), potassium channels (Patel et al, 1999; Thompson and Wafford, 2001; Franks and Honoré, 2004; Gruss et al, 2004; Heurteaux et al, 2004; Grasshoff et al, 2006; Andres-Enguix et al, 2007; Bertaccini and Trudell, 2012), glycine receptors (Mihic et al, 1997; Lobo and Harris, 2005; Dickinson et al, 2007; Bertaccini et al, 2010), and NMDA receptors (Sanders et al, 2003; Dickinson et al, 2007; Dickinson and Franks, 2010). The sites of interaction of general anesthetics with a number of their target membrane proteins are now known with molecular resolution, including their variation in mutant forms of the same proteins (that correlate with changes in anesthetics potency—see e.g., Nury et al, 2011; Stansfeld and Sansom, 2011).…”

“…As part of an ongoing discussion of the importance of transporters in drug distribution that we (Dobson and Kell, 2008; Dobson et al, 2009a,b; Kell and Dobson, 2009; Kell et al, 2011, 2013; Lanthaler et al, 2011; Kell, 2013; Kell and Goodacre, 2014) and others (e.g., Sai and Tsuji, 2004; Shitara et al, 2006; Anderson and Thwaites, 2010; Franke et al, 2010; Giacomini et al, 2010, 2013; Lai et al, 2010; Burckhardt and Burckhardt, 2011; Fromm and Kim, 2011; König, 2011; Mruk et al, 2011; Nies et al, 2011; Thompson, 2011; Tirona, 2011; Zolk and Fromm, 2011; Degorter et al, 2012; Mandery et al, 2012; Riedmaier et al, 2012; Sprowl et al, 2012; Chu et al, 2013b; Estudante et al, 2013; Giacomini and Huang, 2013; Hagenbuch and Stieger, 2013; König et al, 2013; Schlessinger et al, 2013a,b; Tamai and Nakanishi, 2013; Lai and Hsiao, 2014; Sprowl and Sparreboom, 2014) have been highlighting, Smith and colleagues recently published a review (Smith et al, 2014) that claims that the hypothesis that drugs are usually transported into cells via protein carriers is “not a sound scientific principle and lacks experimental evidence.” Smith et al (2014) set out their arguments in considerable detail, and this allows us, in the present publication, to present a contrary view and rehearse the core arguments that pertain to the mechanism(s) of drug and xenobiotic transport across biological membranes.…”

The Accepted “Clinical Interaction Model”: A Special Case of Reality

“…Theoretically, a highly specific treatment should be better tolerated due to an absence of off-target side effects. Unfortunately, practice has shown that there is a poor correlation between in vitro drug effects and in vivo efficacy with target-driven approximations [2,3]. Our increasing understanding of the multiple interacting feedback mechanisms operating within the cell has led to the realization that polypharmacology (the interaction of a single drug on multiple targets or the use of multiple drugs on multiple targets) will be necessary to treat the majority of non-monogenic disorders [4][5][6][7].…”