Fluorine Atoms on C 6 H 5 -Corrole Affect the Interaction with M pro and PL pro Proteases of SARS-CoV-2: Molecular Docking and 2D-QSAR Approaches.

The chymotrypsin-like cysteine protease (3CL pro , also known as main protease-M pro ) and papain-like protease (PL pro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been used as the main targets for screening potential synthetic inhibitors for posterior in vitro evaluation of the most promising compounds. In this sense, the present work reports for the first time the evaluation of the interaction between M pro /PL pro with a series of 17 porphyrin analogues-corrole ( C1 ), meso -aryl-corrole ( C2 ), and 15 fluorinated- meso -aryl-corrole derivatives ( C3 - C17 ) via molecular docking calculations. The impact of fluorine atoms on meso -aryl-corrole structure was also evaluated in terms of binding affinity and physical-chemical properties by two-dimensional quantitative structure-activity relationship (2D-QSAR). The presence of phenyl moieties increased the binding capacity of corrole for both proteases and depending on the position of fluorine atoms might impact positively or negatively the binding capacity. For M pro the para -fluorine atoms might decrease drastically the binding capacity, while for PL pro there was a certain increase in the binding affinity of fluorinated-corroles with the increase of fluorine atoms into meso -aryl-corrole structure mainly from tri-fluorinated insertions. The 2D-QSAR models indicated two separated regions of higher and lower affinity for M pro : C1 - C17 based on dual electronic parameters (σ I and σ R ), as well as one model was obtained with a correlation between the docking score value of M pro : C2 - C17 and the corresponding 13 C nuclear magnetic resonance (NMR) chemical shifts of the sp 2 carbon atoms (δ C-1 and δ C-2 ) of C2 - C17 . Overall, the fluorinated- meso -aryl-corrole derivatives showed favorable in silico parameters as potential synthetic compounds for future in vitro assays on the inhibition of SARS-CoV-2 replication.