Phenolics from the heartwood of Tecoma mollis as potential inhibitors of COVID-19 virus main protease and spike proteins: An In silico study

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging novel coronavirus responsible for the viral pneumonia outbreak (coronavirus disease-19 [COVID-19]) that has impacted millions of people, causing a tremendous global public health concern and number of fatalities. The development of novel antiviral agents is considered an urgent research subject. Objectives: The objective of the study is to discover the phenolic constituents of the methanolic extract of Tecoma mollis Humb. and Bonpl. heartwood and to investigate their potential inhibitory action against SARS-CoV-2 protease and/or entry proteins. Materials and Methods: The heartwood of T. mollis was extracted by maceration with 70% EtOH until complete exhaustion. The extract was concentrated under reduced pressure, mixed with distilled H2O and defatted with CHCl3 to produce a CHCl3 fraction, and then subjected to solvent fractionation with n-butanol to produce an n-butanol fraction. The n-butanol fraction was subjected to a silica gel column using CHCl3-MeOH gradient mixtures followed by reversed-phase high-performance liquid chromatography. The isolated compounds were identified using one- and two-dimensional nuclear magnetic resonance as well as mass spectroscopy. Molecular docking studies have been implemented to identify the binding pattern between ligands and target enzymes, i.e. main protease (Mpro) and spike protein receptor-binding domain (RBD), and compared with the currently used COVID-19 inhibitors. Molecular dynamic simulations have been performed to evaluate the dynamics and stability of protein-ligand complexes. The obtained information is then correlated with the essential structural features, and finally the structure-activity relationship is suggested. Results: Fourteen phenolic glycosides were isolated from the methanolic extract of T. mollis Humb. and Bonpl. heartwood in addition to an iridoid, ixoside. The molecular docking study exhibited that the isolated compounds have a higher binding affinity toward the active site of Mpro and the angiotensin-converting enzyme-2 binding site of spike protein RBD. The phenylpropanoids have higher inhibitory action with higher binding energy toward SARS-CoV-2 Mpro protease as compared to spike protein RBD. Among all the isolated compounds, isoverbascoside (10) exhibited the most potent dual interaction with SARS-CoV-2 Mpro protease and spike protein RBD with high binding energy of − 8.8 and − 7.2 kcal/mol, respe