Discovering selective inhibitors of LOK & SLK kinases with QSAR modeling (2016)
Undergraduates: Christopher Wang, None Stephen Capuzzi None None
Faculty Advisor: Eugene Muratov
Department: Chemistry
"SLK, or STE20-like serine/threonine protein kinase, is an understudied kinase involved in apoptosis and stress fiber dissolution. LOK/STK10, or lymphocyte oriented kinase/serine/threonine protein kinase 10, is thought to be involved in lymphocyte migration and regulation of cell division. To further study the physiological role of these two poorly-studied kinases within cells, there lies a need to discover selective chemical probes. With the advent of High Throughput Screening Assays, there exists a wealth of publicly-accessible chemogenomic data (ChEMBL) on hundreds of kinases that span across the kinome. The goal of this project was to curate and utilize large chemogenomic datasets to build QSAR (Quantative Structural Activty Relationship) models to predict kinase inhibition profiles for untested compounds and to detect the molecules with desired kinase inhibition profiles. Selective inhibitors for kinases SLK and LOK/STK10 were discovered through virtually screening the ZINC database, a curated chemical library of more than a million compounds. Binary random forest QSAR models were constructed on the Caronlina Cheminformatics Workbench with 2489 Dragon molecular descriptors. Selectivity of LOK or SLK was determined from a group of kinases similar in sequence (kinases from the STE20 family) and from kinases with similar activity profiles (TBK1 SRC SYK). "