The promiscuous binding of pharmaceutical drugs and their transporter-mediated uptake into cells: what we (need to) know and how we can do so

A recent paper in this journal sought to counter evidence for the role of transport proteins in effecting drug uptake into cells, and questions that transporters can recognize drug molecules in addition to their endogenous substrates. However, there is abundant evidence that both drugs and proteins are highly promiscuous. Most proteins bind to many drugs and most drugs bind to multiple proteins (on average more than six), including transporters (mutations in these can determine resistance); most drugs are known to recognise at least one transporter. In this response, we alert readers to the relevant evidence that exists or is required. This needs to be acquired in cells that contain the relevant proteins, and we highlight an experimental system for simultaneous genome-wide assessment of carrier-mediated uptake in a eukaryotic cell (yeast).

► Transbilayer diffusion of drugs into cells is probably negligible. ► Drugs use transporters, probably multiple ones, and we need to determine which. ► Both drugs and proteins are highly promiscuous, most proteins bind many drugs and most drugs bind to multiple proteins (on average more than six). ► Mutations in transporters can determine resistance or lack or efficacy. ► The ‘top ten’ small molecules by sales are known to recognise at least one transporter.