Speeding up Early Drug Discovery in Antiviral Research: A Fragment Based in Silico Approach for the Design of Virtual Anti-Hepatitis C Leads

Hepatitis C constitutes an unresolved global health problem. This infectious disease is caused by the hepatotropic hepatitis C virus (HCV), and it can lead to the occurrence of life-threatening medical conditions, such as cirrhosis and liver cancer. Nowadays, major clinical concerns have arisen because of the appearance of multidrug resistance (MDR) and the side effects especially associated with long-term treatments. In this work, we report the first multitasking model for quantitative structure-biological effect relationships (mtk-QSBER), focused on the simultaneous exploration of anti-HCV activity and in vitro safety profiles related to the absorption, distribution, metabolism, elimination, and toxicity (ADMET). The mtk-QSBER model was created from a data set formed by 40 158 cases, displaying accuracy higher than 95% in both training and prediction (test) sets. Several molecular fragments were selected, and their quantitative contributions to anti-HCV activity and ADMET profiles were calculated. By combining the analysis of the fragments with positive contributions and the physicochemical meanings of the different molecular descriptors in the mtk-QSBER, six new molecules were designed. These new molecules were predicted to exhibit potent anti-HCV activity and desirable in vitro ADMET properties. In addition, the designed molecules have good druglikeness according to the Lipinski's rule of five and its variants.