In silico analysis and identification of antiviral coumarin derivatives against 3-chymotrypsin-like main protease of the novel coronavirus SARS-CoV-2

Abstract

Coronavirus disease 2019 (COVID-19) is a pandemic viral disease caused by SARS-CoV-2 that generated serious damages for both the human population and the global economy. Therefore, it is currently considered as one of the most important global health problems of human societies and there is an urgent need for potent drugs or vaccines which can effectively combat this virus. The chymotrypsin-like protease (3CLpro) of SARS-CoV-2 plays a key role in the viral replication inside the host and thus is a promising drug target to design and develop effective antiviral drugs against SARS and other coronaviruses. This study evaluated some antiviral coumarin phytochemicals as potential inhibitors of coronaviruses 3CLpro by in silico approaches such as molecular docking, ADMET prediction, molecular dynamics simulation, and MM-PBSA binding energy calculation. Natural coumarin derivatives were docked to the 3CLpro of SARS-CoV-2 and for further investigation, docked to the 3CLpro of SARS-CoV and MERS-CoV. The docking scores of these natural compounds were compared with 3CLpro referenced inhibitors (ritonavir and lopinavir) and co-crystal inhibitor N3. Molecular docking studies suggested more than half of the coumarin phytochemicals had favorable interaction at the binding pocket of the coronaviruses 3CLpro and exhibited better binding affinities toward 3CLpro than ritonavir and lopinavir. Most antiviral phytochemicals interact strongly with one or both the catalytic dyad residues (His41 and Cys145) and the other key residues of SARS-CoV-2 main protease. Further, MD simulation and binding free energy calculations using MM-PBSA were carried out for three 3CLpro-coumarin complexes and 3CLpro-N3/lopinavir. The results confirmed that the 3CLpro-glycycoumarin, 3CLpro-oxypeucedanin hydrate, and 3CLpro-inophyllum P complexes were highly stable, experience fewer conformation fluctuations and share a similar degree of compactness. Also, the pharmacokinetics and drug-likeness studies showed good results for the selected coumarin phytochemicals.Therefore, the coumarin phytochemicals could be used as antiviral agents in the treatment of COVID-19 after further studies.

Alkaloids and Alkaloid-Like Compounds are Potential Scaffolds of Antiviral Agents against SARS-CoV-2 (COVID-19) Virus

“…molecular docking, molecular dynamics simulation, ADMET prediction, and MM-PBSA binding energy calculation. 87 This investigation revealed that inophyllum P (74), mesuol (75), oxypeucedanin (76), and glycycoumarin (77) showed the highest binding affinity with the best negative energy scores (Figure 18), and they interacted with one or both of His41 and Cys145 residues of 3CLpro through hydrophilic and hydrophobic bonding. 87 These coumarins also had good pharmacokinetics, as well as drug-likeness.…”

“…87 This investigation revealed that inophyllum P (74), mesuol (75), oxypeucedanin (76), and glycycoumarin (77) showed the highest binding affinity with the best negative energy scores (Figure 18), and they interacted with one or both of His41 and Cys145 residues of 3CLpro through hydrophilic and hydrophobic bonding. 87 These coumarins also had good pharmacokinetics, as well as drug-likeness. An independent docking analysis also revealed that glycycoumarin (77) and isodispar B (78) were promising coumarins against COVID-19 virus (Figure 18).…”

“…104 The derivative of beta-lapachone (85), namely ARQ 761, had reached phase I clinical trial for the treatment of cancer, and it exerted the activity through the expression of NAD(P)H:quinone oxidoreductase 1 in cancer cells. 105 The study on virtual screening of 970,000 chemical compounds against the ATP-binding site of Nsp13 helicase ATPase revealed that ergotamine (87) and dihydroergotamine (88) were potential inhibitors of Nsp13 helicase ATPase of SARS-CoV-2 virus (Figure 20). 63 Ergotamine ( 87) is an alkaloid produced by the fungus, Claviceps purpurea, while dihydroergotamine (88) a semi-synthetic derivative prepared from ergotamine (87).…”

A Comprehensive Review about the Molecular Structure of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Insights into Natural Products against COVID-19

“…Several studies have shown that essential oils from medicinal plants, including Citrus spp., Hyssopus officinalis, Illicium spp., mayweeds, tea trees, Mentha spp., Santalum spp., Pinus spp., and certain other aromatic plants, have antiviral properties [258]. Essential oils have the ability to penetrate the lipid bilayer layer of the viral envelope in an abrupt manner, altering the fluidity of the membrane [275]. Because of their lipophilic character, monoterpenes, oxygenated sesquiterpenes, and phenylpropanoids in essential oils can disturb the phospholipid bilayer barrier of human coronaviruses, interfering with the shape of the proteins of enveloped virus throughout the infection [276].…”

Phytochemicals as potential inhibitors for COVID-19 revealed by molecular docking, molecular dynamic simulation and DFT studies

“…The key druggable target of SARS-CoV-2 involves 3-chymotrypsin-like protease (3CL pro ) [39,40], papainlike protease (PL pro ) [41][42][43][44], RNA-dependent RNA polymerase [45], and spike (S) proteins [46,47]. In this work, 6LU7, main protease (M pro ) of COVID-19, crystallized by Liu et al (2020), is used as a potential protein target for the phytochemicals selected.…”