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 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 drug-interacting residues 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 drug-interacting residues identified by NMR chemical shift perturbation and other methods, including residues L ₂₂ WK ₂₄ and Q ₅₂ WFT ₅₅ in the tumor suppressor protein p53. These successes augur well for deciphering the sequence code for IDP-drug binding. DIRseq is available as a web server at <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://zhougroup-uic.github.io/DIRseq/">https://zhougroup-uic.github.io/DIRseq/</ext-link> and has many applications, such as virtual screening against IDPs and designing IDP fragments for in-depth NMR and MD studies.