A ‘rule of 0.5’ for the metabolite-likeness of approved pharmaceutical drugs

Abstract

We exploit the recent availability of a community reconstruction of the human metabolic network (‘Recon2’) to study how close in structural terms are marketed drugs to the nearest known metabolite(s) that Recon2 contains. While other encodings using different kinds of chemical fingerprints give greater differences, we find using the 166 Public MDL Molecular Access (MACCS) keys that 90 % of marketed drugs have a Tanimoto similarity of more than 0.5 to the (structurally) ‘nearest’ human metabolite. This suggests a ‘rule of 0.5’ mnemonic for assessing the metabolite-like properties that characterise successful, marketed drugs. Multiobjective clustering leads to a similar conclusion, while artificial (synthetic) structures are seen to be less human-metabolite-like. This ‘rule of 0.5’ may have considerable predictive value in chemical biology and drug discovery, and may represent a powerful filter for decision making processes.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-014-0733-z) contains supplementary material, which is available to authorized users.

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

“…Consequences of the fact that specific drugs hitchhike on transporters that mainly have intermediary metabolites as their natural substrates Because the natural substrates of these transporters are posited to be (and in many cases clearly are) intermediary metabolites, the principle of molecular similarity implies that successful (i.e., marketed) oral drugs, that necessarily cross biomembranes, will bear structural similarities to at least one metabolite (Figure 3), as has been shown [12,18], and this should be useful in drug design. The structural similarities between marketed drugs and Opinion Trends in Pharmacological Sciences January 2015, Vol.…”

“…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].…”

Control of metabolite efflux in microbial cell factories: current advances and future prospects

“…A specific mass of m/z 144.84 was detected as being particularly taken up in the transporter-containing cells, and this was identified as the dipeptide proline betaine (aka stachydrine), a characteristic constituent of citrus fruits and their juices [206][207][208]. Gründemann and colleagues [184] then performed some elementary cheminformatics (as in [209]) to look for other molecules that were chemically (structurally) similar to stachydrine, recognising that among them was ergothioneine (also known as 2-mercaptohistidine trimethylbetaine; IUPAC name (2S)-3-(2-Thioxo-2,3-dihydro-1H-imidazol-4-yl)-2-(trimethylammonio)propanoate) (Fig 4). When tested individually, ergothioneine turned out to be by far the best substrate, being taken up ~100x more efficiently than was carnitine, and being accumulated ca 180-fold (its uptake was Na + -coupled, presumably with a stoichiometry of at least 2Na + per ergothioneine).…”

Software review: the KNIME workflow environment and its applications in genetic programming and machine learning

“…For cheminformatics (see also [3]), we have been using the KNIME environment [4,5]. KNIME stands for the KonstaNz Information MinEr [1] and is pronounced 'NIME' (with a silent 'K', like knife).…”

“…Thus some rather sophisticated workflows that compared the structures of 'natural' human metabolites with those of marketed drugs and other chemicals, outputting the analysis in the form of a 2D-biclustered heatmap [4,5], were actually just a single workflow with simple filename changes. Given the base workflow, a novice could learn to do these changes in less than an hour, though of course time spent learning to create new workflows can be almost limitless.…”