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Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa.

ABSTRACT: SARS-CoV papain-like protease (PLpro) is an important antiviral target due to its key roles in SARS virus replication. The MeOH extracts of the fruits of the Paulownia tree yielded many small molecules capable of targeting PLpro. Five of these compounds were new geranylated flavonoids, tomentin A, tomentin B, tomentin C, tomentin D, tomentin E (1-5). Structure analysis of new compounds (1-5) by NMR showed that they all contain a 3,4-dihydro-2H-pyran moiety. This chemotype is very rare and is derived from cyclization of a geranyl group with a phenol functionality. Most compounds (1-12) inhibited PLpro in a dose dependent manner with IC50's raging between 5.0 and 14.4 μM. All new compounds having the dihydro-2H-pyran group showed better inhibition than their parent compounds (1 vs 11, 2 vs 9, 4 vs 12, 5 vs 6). In kinetic studies, 1-12 emerged to be reversible, mixed inhibitors.

SUBMITTER: Cho JK

PROVIDER: S-EPMC7126831 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa.

Cho Jung Keun JK Curtis-Long Marcus J MJ Lee Kon Ho KH Kim Dae Wook DW Ryu Hyung Won HW Yuk Heung Joo HJ Park Ki Hun KH

Bioorganic & medicinal chemistry 20130329 11

SARS-CoV papain-like protease (PLpro) is an important antiviral target due to its key roles in SARS virus replication. The MeOH extracts of the fruits of the Paulownia tree yielded many small molecules capable of targeting PLpro. Five of these compounds were new geranylated flavonoids, tomentin A, tomentin B, tomentin C, tomentin D, tomentin E (1-5). Structure analysis of new compounds (1-5) by NMR showed that they all contain a 3,4-dihydro-2H-pyran moiety. This chemotype is very rare and is der ...[more]

PMID: 23623680

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Project description:Background Inhibition of papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is projected to terminate its replication. Hence, these proteases represent viable therapeutic targets. Methods Sixty-one flavonoids with reported activities against other RNA viruses were selected and docked in PLpro and 3CLpro. Flavonoids with better binding energies compared to reference inhibitors (lopinavir and ritonavir) in their interaction with PLpro and 3CLpro were selected for drug-likeness and ADMET analysis. The best representative flavonoid for each protease from the ADMET filtering analysis was subjected to molecular dynamics simulations (MDS) and clustering analysis of the trajectory files. Results Licorice, ugonin M, procyanidin, silymarin, and gallocatechin gallate had better binding energies (-11.8, -10.1, -9.8, -9.7 and -9.6 kcal/mol respectively) with PLpro compared to lopinavir and ritonavir (-9.1 and -8.5 kcal/mol respectively). Also, isonymphaeol B, baicalin, abyssinone II, tomentin A, and apigetrin had better binding energies (-8.7, -8.3, -8.2, -8.1, and -8.1 kcal/mol respectively) with 3CLpro compared to lopinavir and ritonavir (-7.3 and -7.1 kcal/mol respectively). These flavonoids interacted with the proteases via hydrogen and non-hydrogen bonding. Of these flavonoids, silymarin and isonymphaeol B demonstrated most favourable combination of attributes in terms of binding energies, compliance with Lipinski rule for drug-likeness and favourable pharmacokinetics in silico. These two flavonoids exhibited appreciable degree of structural stability, maintaining strong interaction with residues in the different representative clusters selected during the MDS run. Conclusion Silymarin and isonymphaeol B are proposed for further studies as compounds with potential activities against SARS-CoV-2. Supplementary Information The online version contains supplementary material available at 10.1186/s40816-022-00347-y. Highlights • Flavonoids displayed varying affinities for PLpro and 3CLpro of SARS-CoV-2 • They interacted via hydrogen and non-hydrogen bonds; nine and twenty-seven flavonoids had better binding affinities for PLpro and 3CLpro respectively than lopinavir and ritonavir • Silymarin and isonymphaeol B demonstrated most favourable combination of attributes in terms of binding energies, compliance with Lipinski rule for drug-likeness and favourable pharmacokinetics. • Silymarin and isonymphaeol B exhibited appreciable degree of structural stability, maintaining strong interaction with residues in the different representative clusters selected during the MDS run. Supplementary Information The online version contains supplementary material available at 10.1186/s40816-022-00347-y.

Project description:Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys111), through a Michael addition reaction. An inhibition mechanism can therefore be proposed, including four steps: (i) ligand entry into the protease pocket; (ii) Cys111 deprotonation of the thiol group by a Brønsted-Lowry base; (iii) Cys111-S- addition to the ligand; and (iv) proton transfer from the protonated base to the covalently bound ligand. Evaluating the energetics and PLpro conformational changes at each of these steps could aid the design of more efficient and selective covalent inhibitors. For this aim, we have studied by means of MD simulations and QM/MM calculations the whole mechanism. Regarding the first step, we show that the inhibitor entry in the PLpro pocket is thermodynamically favorable only when considering the neutral Cys111, that is, prior to the Cys111 deprotonation. For the second step, MD simulations revealed that His272 would deprotonate Cys111 after overcoming an energy barrier of ca. 32 kcal/mol (at the QM/MM level), but implying a decrease of the inhibitor stability inside the protease pocket. This information points to a reversible Cys111 deprotonation, whose equilibrium is largely shifted toward the neutral Cys111 form. Although thermodynamically disfavored, if Cys111 is deprotonated in close proximity to the vinylic carbon of the ligand, then covalent binding takes place in an irreversible way (third step) to form the enolate intermediate. Finally, due to Cys111-S- negative charge redistribution over the bound ligand, proton transfer from the initially protonated His272 is favored, finally leading to an irreversibly modified Cys111 and a restored His272. These results elucidate the selectivity of Cys111 to enable formation of a covalent bond, even if a weak proton acceptor is available, as His272.

Dataset Information

Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa.

Publications

Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa.

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