Approved drugs predicted to interact with critical residues in the substrate-binding site of SARS-CoV-2 Mpro can be promising inhibitors.

Since late 2019 to early 2020, an outbreak caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has become a worldwide health emergency due to its rapid infection and mortality of millions of people around the world. As the main protease Mpro or 3CLpro produced by the virus plays an important role in coronavirus survival and proliferation, it becomes an excellent drug target to identify COVID-19 inhibitors. Lawsonia inermis L. (henna) is a medicinal plant that has been used for a long time for the treatment of many fungal and bacterial infections. In the search for new anti-COVID agents from medicinal plants, we report the results of our study into the potential inhibition of Mpro by the compounds isolated from the extracts of L. inermis roots and leaves using molecular docking and molecular dynamics simulation. The molecular modeling results showed that all isolated compounds bonded spontaneously into the catalytic pockets of Mpro with binding energies <0. The docking and calculated pharmacokinetic results of the compounds (1-3, 6-8) were similar to and even better than those of the commercial COVID-19 inhibitor remdesivir. In particular, the triterpenoid glycoside suavissimoside R1 (8) showed the best binding to SARS-CoV Mpro, with the lowest binding energy ΔG and IC50,calc. values of −8.19 kcal/mol and 0.98 μM, respectively. Furthermore, the calculations of ADMET (absorption, distribution, metabolism, excretion, and toxicity) showed that it had the lowest toxicity, with a predicted LD50 value of 3320 mg/kg. These triterpenoids are worthy of further study to evaluate their actual bioactivity against SARS-CoV-2 in vitro and in vivo in the hope of contributing valuable scientific data for natural resources for the development novel drug formulations for either the prevention or treatment of COVID-19.

This study contributes to anti-malarial research effort by conducting in silico assessment of 125 compounds originated from Cannabis sativa L. against plasmodium falciparum dihydrofolate reductase-thymidinesynthase (pfDHFR-TS) enzyme for potential inhibition activity. Drug-like and pharmacokinetic criteria were used to assess the drug-like properties of the studied compounds. AutoDock4.2.6 and AutoDock Vina software were used to calculate the possible binding pose of the studied compounds to pfDHFR-TS enzyme. The docking procedure was validated using two known inhibitors cycloguanil and WR99210. 65 out of 125 compounds violated no more than 2 of Lipinski’s rule of five and were sorted out as favorable for drug development. Amongst these 65 compounds, pharmacokinetic properties and toxicity evaluation identified 60 compounds that meet the criteria of drug-like properties and were subjected to further docking studies. Docking outcomes identified 10 compounds including compounds 4, 9, 19, 22, 23, 25, 30, 42, 43, and 59 as potential candidates for inhibiting the function of pfDHFR-TS at the active site through hydrogen bonds with Ile14, Asp54, and Ile 164 residues. Compound 9 is considered as the top “hit” with docking energy far more exceeding those of the standard compounds. High correlation coefficient between the docking energy of AutoDock4.2.6 and AutoDock Vina was recorded with the value of R 2 = 0.74.