News

Titolo: 9-Aminoacridine-based agents impair the bovine viral diarrhea virus (BVDV) replication targeting the RNA-dependent RNA polymerase (RdRp)
Abstract: Bovine viral diarrhea virus (BVDV) infection is still a plague that causes important livestock pandemics. Despite the availability of vaccines against BVDV, and the implementation of massive eradication or control programs, this virus still constitutes a serious agronomic burden. Therefore, the alternative approach to combat Pestivirus infections, based on the development of antiviral agents that specifically inhibit the replication of these viruses, is of preeminent actuality and importance.
Capitalizing from a long-standing experience in antiviral drug design and development, in this work we present and characterize a series of small molecules based on the 9-aminoacridine scaffold that exhibit potent anti-BVDV activity coupled with low cytotoxicity. The relevant viral protein target – the RNA-dependent RNA polymerase – the binding mode, and the mechanism of action of these new antivirals have been determined by a combination of in vitro (i.e., enzymatic inhibition,
isothermal titration calorimetry and site-directed mutagenesis assays) and computational experiments. The overall results obtained confirm that these acridine-based derivatives are promising compounds in the treatment of BVDV infections and, based on the reported structure-activity relationship, can be selected as a starting point for the design of a new generation of improved, safe and selective anti-BVDV agents.

Titolo: Quinoxaline derivatives as new inhibitors of coxsackievirus B5
Abstract: Enteroviruses are among the most common and important human pathogens for which there are no specific antiviral agents approved by the US Food and Drug Administration so far. Particularly, coxsackievirus infections have a worldwide distribution and can cause many important diseases. We here report the synthesis of new 14 quinoxaline derivatives and the evaluation of their cytotoxicity and antiviral activity against representatives of ssRNA, dsRNA and dsDNA viruses. Promisingly, three compounds showed a very potent and selective antiviral activity against coxsackievirus B5, with EC50 in the sub-micromolar range (0.3 - 0.06 μM). A combination of experimental techniques (i.e. virucidal activity, time of drug addition and adsorption assays) and in silico modeling studies were further performed, aiming to understand the mode of action of the most active, selective and not cytotoxic compound, the ethyl 4-[(2,3-dimethoxyquinoxalin-6-yl)methylthio]benzoate (6).

Titolo: Triazolopyridinyl-acrylonitrile derivatives as antimicrotubule agents: Synthesis, in vitro and in silico characterization of antiproliferative activity, inhibition of tubulin polymerization and binding thermodynamics
Abstract: In this paper we report the synthesis, in vitro anticancer activity, and the experimental/computational characterization of mechanism of action of a new series of E isomers of
triazolo[4,5-b/c]pyridin-acrylonitrile derivatives (6c-g, 7d-e, 8d-e, 9c-f, 10d-e, 11d-e). All new compounds are endowed with moderate to interesting antiproliferative activity against 9 different cancer cell lines derived from solid and hematological human tumors. Fluorescence-based assays prove that these molecules interfere with tubulin polymerization. Furthermore, isothermal titration calorimetry (ITC) provides full tubulin/compound binding thermodynamics, thereby ultimately qualifying and quantifying the interactions of these molecular series with the target protein. Lastly, the analysis based on the tight coupling of in vitro and in silico modelling of the interactions
between tubulin and the title compounds allows to propose a molecular rationale for their biological activity.

Titolo: Materials by design: multiscale molecular modeling for the design of nanostructured membranes
Abstract: The fast development of digitalization and computational science is opening new possibilities for a rapid design of new materials. Computational tools coupled with focused experiments can be successfully used for the design of new nanostructured materials in different sectors, including membrane engineering. Accordingly, in this Chapter, we present the application of a multiscale molecular simulation protocol for predicting gas transport properties in polymeric nanocomposite membranes constituted by titania (TiO2) nanoparticles dispersed in thermoplastic polyurethanes (TPUs). The Chapter starts with a general introduction on the future of computational tools for the design of new materials and introduces the paradigm underlying of multiscale molecular modelling. It then continues with the description of the multiscale (i.e., atomistic, mesoscale and finite element calculations) computational recipe developed ad hoc for the prediction of different gas permeation and diffusion in TPU/TiO2 nanocomposite membranes. Finally, the comparison of in silico and experimental results on these systems is reported and discussed. The quality of the agreement obtained between virtual and real data for such complex systems indeed confirms the validity of computational tools for the design and transport property prediction of nanocomposite membranes for gas treatment.