RESUMEN
In vitro cell-line cytotoxicity is widely used in the experimental studies of potential antineoplastic agents and evaluation of safety in drug discovery. In silico estimation of cytotoxicity against hundreds of tumor cell lines and dozens of normal cell lines considerably reduces the time and costs of drug development and the assessment of new pharmaceutical agent perspectives. In 2018, we developed the first freely available web application (CLC-Pred) for the qualitative prediction of cytotoxicity against 278 tumor and 27 normal cell lines based on structural formulas of 59,882 compounds. Here, we present a new version of this web application: CLC-Pred 2.0. It also employs the PASS (Prediction of Activity Spectra for Substance) approach based on substructural atom centric MNA descriptors and a Bayesian algorithm. CLC-Pred 2.0 provides three types of qualitative prediction: (1) cytotoxicity against 391 tumor and 47 normal human cell lines based on ChEMBL and PubChem data (128,545 structures) with a mean accuracy of prediction (AUC), calculated by the leave-one-out (LOO CV) and the 20-fold cross-validation (20F CV) procedures, of 0.925 and 0.923, respectively; (2) cytotoxicity against an NCI60 tumor cell-line panel based on the Developmental Therapeutics Program's NCI60 data (22,726 structures) with different thresholds of IG50 data (100, 10 and 1 nM) and a mean accuracy of prediction from 0.870 to 0.945 (LOO CV) and from 0.869 to 0.942 (20F CV), respectively; (3) 2170 molecular mechanisms of actions based on ChEMBL and PubChem data (656,011 structures) with a mean accuracy of prediction 0.979 (LOO CV) and 0.978 (20F CV). Therefore, CLC-Pred 2.0 is a significant extension of the capabilities of the initial web application.
Asunto(s)
Antineoplásicos , Programas Informáticos , Humanos , Teorema de Bayes , Antineoplásicos/farmacología , Antineoplásicos/química , Prednisona , Línea Celular TumoralRESUMEN
The alternative splicing is a mechanism increasing the number of expressed proteins and a variety of these functions. We uncovered the protein domains most frequently lacked or occurred in the splice variants. Proteins presented by several isoforms participate in such processes as transcription regulation, immune response, etc. Our results displayed the association of alternative splicing with branched regulatory pathways. By considering the published data on the protein proteins encoded by the 18th human chromosome, we noted that alternative products display the differences in several functional features, such as phosphorylation, subcellular location, ligand specificity, protein-protein interactions, etc. The investigation of alternative variants referred to the protein kinase domain was performed by comparing the alternative sequences with 3D structures. It was shown that large enough insertions/deletions could be compatible with the kinase fold if they match between the conserved secondary structures. Using the 3D data on human proteins, we showed that conformational flexibility could accommodate fold alterations in splice variants. The investigations of structural and functional differences in splice isoforms are required to understand how to distinguish the isoforms expressed as functioning proteins from the non-realized transcripts. These studies allow filling the gap between genomic and proteomic data.