In silico identification of novel curcumin derivatives as potential inhibitors against SARS-CoV-2 enzymes


In a recently published study in the Journal of Computational Biology and Chemistryresearchers identified curcumin derivatives as potential inhibitors of coronavirus-2 (SARS-CoV-2) severe acute respiratory syndrome enzymes.

Learn: Design and various in silico studies of the novel curcumin derivatives as potential candidates against COVID-19-associated major enzymes. Credit: Natthapol Siridech/Shutterstock

The 2019 coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2 has wreaked havoc around the world over the past two years, with over 458 million infections and more than 6 million deaths recorded so far, according to the World Health Organization (WHO). ) records. Researchers from different regions have been looking for ways to stem the spread of the virus and develop effective therapeutic strategies to treat those infected. Vaccination is by far the most effective strategy to contain the clinical severity of COVID-19.

Although several antiviral drugs are used alone or in combination to treat COVID-19, a fully effective therapy is still not available. SARS-CoV-2 activity is inhibited by inhibiting its binding to host cell receptors or by blocking its replication machinery. In this regard, several research groups have tirelessly explored drugs with inhibitory activity against SARS-CoV-2 enzymes.

In addition to chemical drugs, phytochemicals are reportedly inhibitors of coronaviruses. While the development of a new drug can be tedious, repurposing existing chemical drugs and phytochemicals or synthesizing their derivatives with appropriate pharmacological properties could be quick and prove effective.

The study

The present study examined the inhibitory potential of curcumin derivatives on SARS-CoV-2 enzymes. Curcumin is one of the curcuminoids found in turmeric, a plant known for its herbal properties.

The authors created a library of 68 (synthetic) curcumin derivatives and filtered them to remove molecules with poor absorption, distribution, metabolism and excretion (ADME) profiles. The selected molecules were subjected to molecular docking studies, followed by molecular dynamics (MD) simulations and molecular-mechanical Poisson-Boltzmann surface analysis (MM-PBSA).

Researchers found 22 candidate molecules that are 2 H-pyran-4(3 H)-one and 1-methylpiperidin-4-one derivatives of curcumin with reliable ADME profiles using five drug filters – Lipinski- , Ghose, Veber, Egan and Muegge filters . They found that the ADME properties of these candidate drugs exceeded those of various reference drugs and known inhibitors.

A brain or gut permeation map (BOILED-Egg) was obtained from the Swiss ADME server. It contained two ellipses – white and yellow; the compounds in the yellow area are most likely to be absorbed into the gastrointestinal tract. Those in the white region are more likely to be absorbed into the brain and gastrointestinal tract. Many reference inhibitors were outside of the “egg”, ie white and yellow regions. Of the 22 candidate molecules, 19 were found within the yellow ellipse and reference drugs such as lopinavir, 7i, 8k favipiravir, 7k and phytochemicals such as curcumin and its derivatives were observed in the white zone.

Docking analysis revealed a higher affinity of the candidate molecules for binding to the papain-like protease (PLprofessional) than other SARS-CoV-2 enzymes. Two (candidate) compounds, 7h (-8.3 kcal/mol) and 8h (-8.4 kcal/mol), had the highest binding affinity for the major protease (Mprofessional), which exceeds that of N3 (-8.0 kcal/mol) and remdesivir (-8.1 kcal/mol), which are known to induce Mprofessional Inhibitors.

Similarly, curcumin derivatives showed higher binding affinities to RNA-dependent RNA polymerase (RdRp) than reference drug and F86, a known RdRp inhibitor. Docking scores were higher for spike (S) protein and its human receptor, angiotensin-converting enzyme-2 (ACE2) complex (S:ACE2), than for S protein alone. For the complex, the natural inhibitor cobophenol A had the highest affinity (-11.15 kcal/mol) than curcumin (-8.42 kcal/mol).

MD simulations were performed on the PLprofessional Enzyme, since many curcumin derivatives have a higher binding affinity to this protein. In a 100 nanosecond (ns) MD simulation, VIR250 (PLprofessional Inhibitor) and remdesivir (reference) were used together with seven curcumin derivatives (8b, 8c, 8d, 8f, 8g, 8h and 8k) as ligands. All nine ligands had a significant inhibitory effect on protein conformation, and the curcumin derivatives consistently had higher binding energies than either VIR250 or remdesvir. Several hot and non-hot amino acid residues were observed in PLProfessional, probably involved in inhibiting its activity.


The present study examined different curcumin derivatives with inhibitory potential against SARS-CoV-2 enzymes and observed that PLprofessional showed the highest binding affinity to various drug candidates. Docking of PLprofessional showed significantly higher affinity for curcumin derivatives (8h and 8g) than reference drug or its inhibitor (VIR250), including natural curcuminoids.

MM-PBSA analysis identified PLprofessional Residues such as K157, E161, D164, R166, M208, P247, P248, Y264, Y273 and D302 are involved in ligand-protein binding. Taken together, these results suggest that curcumin derivatives could act as potential inhibitors of the main enzymes of SARS-CoV-2.


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