MacAinsh, M.; Qin, S.; Zhou, H.-X.

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 L22WK24 and Q52WFT55 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.