Protein-Ligand Docking Simulations with AutoDock4 Focused on the Main Protease of SARS-CoV-2.

BACKGROUND: The main protease of SARS-CoV-2 (Mpro) is one of the targets identified in SARS-CoV-2, the causative agent of COVID-19. The application of X-ray diffraction crystallography made available the three-dimensional structure of this protein target in complex with ligands, which paved the way for docking studies. OBJECTIVE: Our goal here is to review recent efforts in the application of docking simulations to identify inhibitors of the Mpro using the program AutoDock4. METHODS: We searched PubMed to identify studies that applied AutoDock4 for docking against this protein target. We used the structures available for Mpro to analyze intermolecular interactions and reviewed the methods used to search for inhibitors. RESULTS: The application of docking against the structures available for the Mpro found ligands with an estimated inhibition in the nanomolar range. Such computational approaches focused on the crystal structures revealed potential inhibitors of Mpro that might exhibit pharmacological activity against SARS-CoV-2. Nevertheless, most of these studies lack the proper validation of the docking protocol. Also, they all ignored the potential use of machine learning to predict affinity. CONCLUSION: The combination of structural data with computational approaches opened the possibility to accelerate the search for drugs to treat COVID-19. Several studies used AutoDock4 to search for inhibitors of Mpro. Most of them did not employ a validated docking protocol, which lends support to critics of their computational methodology. Furthermore, one of these studies reported the binding of chloroquine and hydroxychloroquine to Mpro. This study ignores the scientific evidence against the use of these antimalarial drugs to treat COVID-19.

Identification of a tyrosine phosphatase involved in the response to mechanical injury in leaves of Ricinus communis.

Plants defend themselves against biotic or abiotic stress by triggering intracellular signaling pathways that regulate gene expression and responses to the offending agent. Phosphorylation and dephosphorylation represent major mechanisms for the regulation of plant defense pathways. Therefore, MAP kinases and phosphatases have been the focus of many studies in this area. This study identified three phosphatase activities, namely RcPPase I, II and III. Wounding increased the activity levels of RcPPase III, while the activities of RcPPase I and II remained constant compared to the control. N-terminal partial amino acid sequence, biochemical characterization with use of specific substrates and inhibitors indicated that the RcPPase III belong to the family of tyrosine phosphatases (PTPs).

Methyl jasmonate promotes the transient reduction of the levels of 2-Cys peroxiredoxin in Ricinus communis plants.

Jasmonates are signaling molecules that play a key role in the regulation of metabolic processes, reproduction and defense against insects and pathogens. This study investigated the effects of methyl jasmonate on the protein pattern of Ricinus communis plants and the activity of guaiacol peroxidase, an antioxidant enzyme. Methyl jasmonate treatment caused a transient reduction in guaiacol peroxidase activity. A similar response was observed for the levels of 2-Cys peroxiredoxin protein. Moreover, the levels of the small and large chains of Rubisco were also reduced. The transient reduction of the levels and activity of antioxidant enzymes could account for the increase in the levels of H2O2, an important signaling molecule in plant defense.