How Far Are We from the Rapid Prediction of Drug Resistance Arising Due to Kinase Mutations?

In all living organisms, protein kinases regulate various cell signaling events through phosphorylation. The phosphorylation occurs upon transferring an ATP's terminal phosphate to a target residue. Because of the central role of protein kinases in several proliferative pathways, point mutations occurring within the kinase's ATP-binding site can lead to a constitutively active enzyme, and ultimately, to cancer. A select set of these point mutations can also make the enzyme drug resistant toward the available kinase inhibitors. Because of technical and economical limitations, rapid experimental exploration of the impact of these mutations remains to be a challenge. This underscores the importance of kinase-ligand binding affinity prediction tools that are poised to measure the efficacy of inhibitors in the presence of kinase mutations. To this end, here, we compare the performances of six web-based scoring tools (DSX-ONLINE, KDEEP, HADDOCK2.2, PDBePISA, Pose&Rank, and PRODIGY-LIG) in assessing the impact of kinase mutations on their interactions with their inhibitors. This assessment is carried out on a new structure-based BINDKIN benchmark we compiled. BINDKIN contains wild-type and mutant structure pairs of kinase-inhibitor complexes, together with their corresponding experimental binding affinities (in the form of IC