DIRseq: a method for predicting drug-interacting residues of intrinsically disordered proteins from sequences

Intrinsically disordered proteins (IDPs) are now well-recognized as drug targets. Identifying drug-interacting residues (DIRs) is valuable for both optimizing compounds and elucidating the mechanism of action. Currently, NMR chemical shift perturbation and all-atom molecular dynamics (MD) simulations are the primary tools for this purpose. Here we present DIRseq, a fast method for predicting DIRs from the amino-acid sequence. All residues contribute to the propensity of a particular residue to be drug-interacting; the contributing factor of each residue has an amplitude that is determined by its amino-acid type and attenuates with increasing sequence distance from the particular residue. DIRseq predictions match well with DIRs identified by NMR chemical shift perturbation and other methods, including residues L ₂₂ WK ₂₄ and Q ₅₂ WFT ₅₅ in the tumor repressor protein p53. These successes augur well for deciphering the sequence code for IDP-drug binding. DIRseq is available as a web server at https://zhougroup-uic.github.io/DIRseq/ and has many applications, such as virtual screening against IDPs and designing IDP fragments for in-depth NMR and MD studies.