Study Of Computer-aided Kinase Inhibitor Design And Structure-Activity Relationship Visualization Analysis

Computer technology,including molecular docking,virtual screening and visualization analysis plays an important role in drug research and development.Using molecular docking,5H-pyrrolo[3,2-d]pyrimidine was identified as a potential core structure for kinase inhibitors.Based on the findings,we constructed a compound library of 73 compounds using fragment-based design and derivatization.The identification of potent kinase inhibitors using antiproliferative assays against a panel of kinase-transfored Ba/F3 cell lines indicates the success of 5H-pyrrolo[3,2-d]pyrimidine-based compound library design.PLK1(Polo-like kinase 1),a serine/threonine kinase plays pivotal role in a variety of cellular activities.It’s believed that PLK1 could be a potential target for cancer therapy.A series of 2,4-diamino-5-substitued-pyrimidine compounds were designed based on molecular docking and synthesized to target PLK1.Among this series of compounds,2-32 was emerged with the best inhibitory activity against PLK1 in biochemical assay with an IC50 lower than 0.508 nmol·L-1.It also showed potent anti-proliferation activities against a variety of cancer cell lines.Further mechanism study revealed the on-target effect of 2-32.This compound induced cell-cycle arrest at mitotic(M)phase by inhibiting PLK1 kinase activity,which leads to apoptosis.Computer-aided structure-activity relationship(SAR)analysis includes both molecular docking and SAR visualization.A practical and effective visualization method was developed using only R,ggplot2,RStudio and Excel to better explore the structure-activity relationship hidden in the massive data generated by compound screening.The method was successfully put into use to explore the SAR of an in-house compound library against RET kinase,which leads to the discovery of a novel "combinational" effect of SAR.Further molecular docking study provided the interpretation of such finding.In summary,we succeeded in constructing novel compound library,designing potent PLK1 kinase inhibitors and analyzing complex SAR of the massive in-house RET inhibitor library through the combination of computer technology and experimental approach.