APPLICATION OF COMPUTATIONAL METHODS FOR THE IDENTIFICATION OF NEW DDX3X INHIBITORS

The search for new antiviral drugs for the treatment of clinical and emerging viruses is a delicate task. Drugs available today are developed to target a specific virus or viral strain, and only few prophylactics show a broad-spectrum activity that can be used to treat drug-resistant infections or in case of emergencies. Among the strategies that can be pursued to search for new antiviral drugs, there is the inhibition of a host protein involved in the viral replication cycle. The inhibition of DDX3X, a human ATP-dependent RNA helicase, allowed to discover the first broad-spectrum antiviral compound able to inhibit the replication of HIV resistant strains, HCV and of emerging viruses like West Nile Virus, Japanese Encephalitis Virus, Dengue Virus. In this project, several computational strategies have been applied to improve the biodistribution and pharmacokinetic properties of this compound and a fluorescent inhibitor was designed to understand the mode of action of DDX3X inhibitors in DENV infected cells. The selective inhibition of DDX3X can be pursued targeting a small pocket, peculiar to the human protein, called unique motif (UM). The study of the interactions established by the first active compound within UM, allowed to identify the amino acids responsible of its activity. Considering these findings, a small library of derivatives able to establish the fundamental interactions with the UM was designed. Moreover, a pharmacophore-based virtual screening procedure allowed to discover new compounds that will be biologically evaluated as new UM inhibitors. PROTAC is instead a potent strategy to target protein degradation. A PROTAC molecule, that is constituted by two active moieties hold together by a linker, allow the selective ubiquitination and degradation of the protein of interest by the proteasome. In this contest, the application of computational procedures on known SOCS2 binders, allowed to establish a SAR that will be used to design novel derivatives that can be used both as inhibitors of the protein and as binders of the E3 ligase. A pharmacophore-based virtual screening performed on the Elongin C allowed to discover new compounds that will be biologically evaluated to establish if they can be used as E3 ligase binders.