RESUMO
In the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic, numerous attempts have been made to discover new potential antiviral molecules against its causative agent, SARS-CoV-2, many of which focus on its main protease (Mpro). We hereby used two approaches based on molecular docking simulation to explore the interaction of four libraries of semisynthetic nitrogenous heterocyclic compounds with Mpro. Libraries L1 and L2 contain 52 synthetic derivatives of the natural compound 2-propylquinoline, whereas libraries L3 and L4 contain 65 compounds synthesized using the natural compound physostigmine as a precursor. Validation through redocking suggested that the rigid receptor and flexible receptor approaches used for docking were suitable to model the interaction of this type of compounds with the target protein, although the flexible approach seemed to provide a more realistic representation of interactions within the active site. Using empirical energy score thresholds, we selected 58 compounds from the four libraries with the most favorable energy estimates. Globally, favorable estimates were obtained for molecules with two or more substituents, putatively accommodating in three or more subsites within the Mpro active site. Our results pave the way for further experimental evaluation of the selected compounds as potential antiviral agents against SARS-CoV-2.
Assuntos
Antivirais/química , Tratamento Farmacológico da COVID-19 , COVID-19 , Proteases 3C de Coronavírus , Compostos Heterocíclicos/química , Simulação de Dinâmica Molecular , Pandemias , Inibidores de Proteases/química , SARS-CoV-2/enzimologia , Antivirais/uso terapêutico , COVID-19/epidemiologia , Domínio Catalítico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Compostos Heterocíclicos/uso terapêutico , Humanos , Inibidores de Proteases/uso terapêuticoRESUMO
Alzheimer's disease (AD) is the most common form of dementia among the elderly and has become a leading public health concern worldwide. It represents a huge economic and psychological burden to caregivers and families. The presence of extracellular amyloid beta (Aß) plaques is one of the hallmarks of this neurodegenerative disorder. Amyloid plaques are comprised of aggregates of Aß peptides, mainly Aß42, originated by the cleavage of the amyloid precursor protein (APP). Aß is a crucial target for the treatment of AD, but to date, no effective treatment for the clearance of Aß has been found. We have identified four new hexahydropyrroloindoles (HPI) synthetic compounds that are able to inhibit the aggregation of Aß42 and/or disaggregate the fibril. Docking experiments suggest that the nonpolar component of the interaction of compounds with Aß42 contributes favorably to the binding free energy of each complex. Molecular dynamics simulations suggested fibril disaggregating activity of compounds 1 via interaction with hydrophobic moieties of the fibril. Consistently, compounds 1 and 2 were able to mitigate Aß42 fibrils induced death in rat pheochromocytoma cells (PC 12). One of the compounds reduces the formation of Aß aggregates in vivo and the paralysis associated with Aß toxicity in Caenorhabditis elegans. Our study thus augments efforts for the identification and characterization of new agents that may help stop or delay the progression of AD.