A general pattern for substrate recognition by P‐glycoprotein

P‐glycoprotein actively transports a wide variety of chemically diverse compounds out of the cell. Based on a comparison of a hundred compounds previously tested as P‐glycoprotein substrates, we suggest that a set of well‐defined structural elements is required for an interaction with P‐glycoprotein. The recognition elements are formed by two (type I unit) or three electron donor groups (type II unit) with a fixed spatial separation. Type I units consist of two electron donor groups with a spatial separation of 2.5 ± 0.3 Å. Type II units contain either two electron donor groups with a spatial separation of 4.6 ± 0.6 Å or three electron donor groups with a spatial separation of the outer two groups of 4.6 ± 0.6 Å. All molecules that contain at least one type I or one type II unit are predicted to be P‐glycoprotein substrates. The binding to P‐glycoprotein increases with the strength and the number of electron donor or hydrogen bonding acceptor groups forming the type I and type II units. Correspondingly, a high percentage of amino acids with hydrogen bonding donor side chains is found in the transmembrane sequences of P‐glycoprotein relevant for substrate interaction. Molecules that