Abstract

The ubiquitin-proteasome pathway (UPP) is the primary degradation system of short-lived regulatory proteins. Cellular processes such as the cell cycle, signal transduction, gene expression, DNA repair and apoptosis are regulated by this UPP and dysfunctions in this system have important implications in the development of cancer, neurodegenerative, cardiac and other human pathologies. UPP seems also to be very important in the function of eukaryote cells of the human parasites like Plasmodium falciparum, the causal agent of the neglected disease Malaria. Hence, the UPP could be considered as an attractive target for the development of compounds with Anti-Malarial or Anti-cancer properties. Recent online databases like ChEMBL contains a larger quantity of information in terms of pharmacological assay protocols and compounds tested as UPP inhibitors under many different conditions. This large amount of data give new openings for the computer-aided identification of UPP inhibitors, but the intrinsic data diversity is an obstacle for the development of successful classifiers. To solve this problem here we used the Bob-Jenkins moving average operators and the atom-based quadratic molecular indices calculated with the software TOMOCOMD-CARDD (TC) to develop a quantitative model for the prediction of the multiple outputs in this complex dataset. Our multi-target model can predict results for drugs against 22 molecular or cellular targets of different organisms with accuracies above 70% in both training and validation sets.

Keywords: UPP inhibitor, Cancer, Malaria, CHEMBL, multi-target, multi-scale and multi-output model, moving average; QSAR, atom-based quadratic indices.

Graphical Abstract