Metodi In Silico applicati allo sviluppo di nuove molecole attive verso NLRP3 inflammasoma

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 impacted world-wide leading to harsh consequences as healthcare emergencies, quarantines and millions of deaths. The acute phase of infection mainly interests the respiratory tract with symptoms as cough, sore throat, anosmia and ageusia, while potentially lethal pulmonary disfunctions have been largely reduced by massive vaccinations. Contrarily, increasing evidence showed that COVID-19 could lead to neurological and psychiatric disorders especially for elderly people and individuals with pre-existing inflammatory conditions. Indeed, closely with other coronaviruses, SARS-CoV-2 overruns central nervous systems (CNS), likely passing through damaged blood brain barrier or through neuronal retrograde route, where it can act as a trigger for inflammatory complexes known as inflammasomes. Involvement of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is consistent with several studies which demonstrated that SARS-CoV-2 expresses almost one protein able to spark it. Indeed, NLRP3 is a protein hub which regulates for different inflammation pathways, and it is responsive to a wide range of either endogenous or exogenous triggers. Hyperactivation of NLRP3 leads to a higher level of circulating cytokines, mainly IL-1β and IL-18, and to the release of active form of gasdermin-D (GSDMD-n), which is the effector of a type of programmed cell death known as pyroptosis. This scenario leads to detrimental effects at CNS, which manifest in patients with debilitating encephalopathies, as well as increased risks of developing other neurodegenerative diseases marked by brain inflammation (e.g., Alzheimer’s disease, Parkinson disease). For these reasons, NLRP3 inflammasome represents an interesting target for developing first-line drugs for a variety of conditions on which levels of this protein are augmented. Furthermore, in silico methods could provide clarifications about the mechanism of action as well as the structure-activity relationship and optimization of novel classes of NLRP3 inhibitors.