Virtual screening campaigns and ADMET evaluation to unlock the potency of flavonoids from Erythrina as 3CLpro SARS-COV-2 inhibitors

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) pandemic with more than 6 million deaths worldwide. Flavonoids from the genus Erythrina may inhibit SARS-CoV-2, targeting 3C-like protease (3CL pro ), an enzyme essential in the virus's growth. Hence, this study aimed to screen 378 flavonoids from Erythrina against 3CL pro , using molecular docking, Lipinski's rule of five, and in silico absorption, distribution, metabolism, excretion, and toxicity. These virtual screening campaigns suggest that 108 flavonoids have stronger binding energy values (−13.23 to −10.20 kcal/mol) than the N3 inhibitor (−10.14 kcal/mol) as the reference ligand. Some 33 of these flavonoids may be hepatoxicity-and mutagenicity-free. They are also non-hERG I and II inhibitors. Two of them, orientanol E (171) and erycaffra F (57), have binding energy values in the top 10 hits and good absorption profiles, despite their poor distribution properties. They may have a high bioavailability in the body and be excreted from the body through feces. Conducted molecular dynamics simulations also support orientanol E (171) and erycaffra F (57) as 3CL pro inhibitor candidates. Our study suggests that flavonoids from Erythrina have potential as 3CL pro inhibitors, which help guide further in vitro and in vivo experiments in COVID-19 drug development.

Bioinformatics Study of Flavonoids From Genus Erythrina As Ace2 inhibitor Candidates For Covid-19 Treatment

“…From the molecular docking result, compound 310 is predicted to have lower binding energy toward ACE2 than compound 471 ( Table 1 ), whereas the molecular dynamics simulation suggested the opposite (−15.9612 ± 1.9765 and −18.1921 ± 2.6197 kcal/mol respectively for compounds 310 and 471, expressed as median ± SD) The difference of binding energy value obtained from molecular docking and MD simulation may due to the ability of MD simulation to accommodate complete flexibility of ligand and protein, therefore allowing intermolecular interaction adjustment. 18 , 22

Figure 1 Comparative ΔG MMGBSA profiles for compounds 310 and 471 every 10 ns over 100 ns simulation time. Compound 310 shows relatively stable free energy values around −16 Kcal/mol, whereas compound 471 exhibits more fluctuation, indicating differing stabilities in their interactions with the target.

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“…The method is considered valid if the root mean square deviation (RMSD) is less than 2.00 Å. 18 , 22 …”

“…From the molecular docking result, compound 310 is predicted to have lower binding energy toward ACE2 than compound 471 (Table 1), whereas the molecular dynamics simulation suggested the opposite (−15.9612 ± 1.9765 and −18.1921 ± 2.6197 kcal/mol respectively for compounds 310 and 471, expressed as median ± SD) The difference of binding energy value obtained from molecular docking and MD simulation may due to the ability of MD simulation to accommodate complete flexibility of ligand and protein, therefore allowing intermolecular interaction adjustment. 18,22 In addition to the MMGBSA free energy calculation, we also conducted RMSD calculations to evaluate the ACE2 protein stability upon the binding of compounds 310 and 471. The RMSD profile (Figure 2) of the Cα atoms remained stable at average value of 1.59 ± 0.22 Å with interquartile range (IQR) of 0.25 Å for 310-ACE2 complex and 1.65 ± 0.19 Å (IQR 0.23 Å) for 310-ACE2 complex.…”

“… 14 In the field of drug discovery and development, virtual screening allows for the identification of potential ligands from a large database of chemical structures using computational processes, 15 minimizes the timeline of drug design and discovery by screening a large number of compounds within a short span of time, 16 and helps narrow the focus to the most promising candidates, thereby optimizing the use of time, money, and laboratory resources. 17 Recent literature has highlighted the application of virtual screening in the discovery of drugs for COVID-19 treatment, 16 , 18 therefore, in this study, we employed structure-based virtual screening to determine the potency of flavonoids from the genus Erythrina as candidate drugs for COVID-19 treatment through the inhibition of the ACE2 receptor.…”

Virtual Screening and ADMET Prediction to Uncover the Potency of Flavonoids from Genus Erythrina as Antibacterial Agent through Inhibition of Bacterial ATPase DNA Gyrase B

“…This is an important step for an in silico docking experiment because it can increase the accuracy and reliability of the experiment [33]. A molecular docking protocol is valid if the RMSD of the docked ligand is less than 2 Å [34]. In our experiment, we obtained an RMSD value of 1.72 Å; therefore, our docking protocol is valid and can be employed to virtually screen the potency of flavonoids from genus Erythrina as an inhibitor of bacterial ATPase DNA gyrase B.…”