Affiliation:
1. National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine 138 Xianlin Road 210023 Nanjing, Jiangsu China
2. Laboratory of Molecular Design and Drug Discovery School of Science China Pharmaceutical University 639 Longmian Avenue 211198 Nanjing, Jiangsu China
3. School of Chemistry and Chemical Engineering Shanghai University of Engineering Science 201620 Shanghai China
Abstract
AbstractKinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost‐effective in silico prediction of KIs drug repositioning via analyzing cross‐docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross‐docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT‐PI3K‐mTOR pathway with IC50 values of 3.3, 3.2 and 5.8 μM. Further cell assays showed IC50 values of 0.2, 1.2 and 0.6 μM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible.