Integration of fingerprint-based similarity searching and kernel-based partial least squares analysis to predict...

Fingerprint-based similarity searching is an important strategy for virtual screening in drug discovery. In the present study, we carried out a systematic virtual screening study, followed by the establishment of kernel-based partial least square (KPLS) analysis prediction models for five tyrosine kinase drug targets, C-terminal SRC kinase (CSK), human epidermal growth factor 2 (HER2), and Janus kinases 1, 2, and 3 (JAK1, JAK2, and JAK3), using a dataset of 3688 compounds. These kinases are important drug discovery targets, particularly as HER2 has been validated for the treatment of metastatic breast cancer, JAK inhibitors have been validated for the clinical management of arthritis and autoimmune diseases, and CSK has been found to play an important role in bone remodeling in arthritis. We conducted similarity screenings with the most active molecule for each target in the dataset as a query using eight (8) types of two-dimensional (2D) molecular fingerprints, comprising seven Hashed fingerprints, Linear, Dendritic, Radial, Pairwise, Triplet, Torsion, and MOLSPRINT2D, and one Structural keys fingerprint, MACCS. The top ranked 1% of compounds from each target's similarity screening results was used to set up kernel-based partial least square (KPLS) prediction models, with q² values up to 0.8. The best KPLS model for each target was selected based on its predictive ability and boot strapping results and used for prediction. This integrated study approach combining similarity screening with KPLS analysis has a high potential to enhance the accuracy and efficiency of virtual screening and thus improve the drug discovery process.