Design and various in silico studies of the novel curcumin derivatives as potential candidates against COVID-19 -associated main enzymes

Abstract

The novel coronavirus disease (COVID-19) is a highly contagious disease caused by the SARS-CoV-2 virus, leading severe acute respiratory syndrome in patients. Although various antiviral drugs and their combinations have been tried so far against SARS-CoV-2 and they have shown some effectiveness, there is still a need for safe and cost-effective binding inhibitors in the fight against COVID-19. Therefore, phytochemicals in nature can be a quick solution due to their wide therapeutic spectrum and strong antiviral, anti-inflammatory, and antioxidant properties. In this context, the low toxicity, and high pharmacokinetic properties of curcumin, which is a natural phytochemical, as well as the easy synthesizing of its derivatives reveal the need for investigation of its various derivatives as inhibitors against coronaviruses. The present study focused on curcumin derivatives with reliable ADME profile and high molecular binding potency to different SARS-CoV-2 target enzymes (3CLPro, PLpro, NSP7/8/12, NSP7/8/12 +RNA, NSP15, NSP16, Spike, Spike+ACE). In the molecular docking studies, the best binding scores for the 22 proposed curcumin derivatives were obtained for the PLpro protein. Furthermore, MD simulations were performed for high-affinity ligand-PLpro protein complexes and subsequently, Lys157, Glu161, Asp164, Arg166, Glu167, Met208, Pro247, Pro248, Tyr264, Tyr273 and Asp302 residues of PLpro was determined to play key role for ligand binding by Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis. The results of the study promise that the proposed curcumin derivatives can be potent inhibitors against SARS-CoV-2 and be converted into pharmaceutical drugs. It is also expected that the findings may provide guiding insights to future design studies for synthesizing different antiviral derivatives of phytochemicals.

Keywords: Coronavirus; Curcumin; Docking; Drug design; MM-PBSA; Molecular dynamic; SARS-CoV-2; Simulation.

Graphical abstract

Scheme 1

The Representation of curcumin analogues and its 2 H-pyran-4(3 H)-one and 1-methylpiperidin-4-one derivatives.

Fig. 1

The map of BOILED-Egg for all compounds. Here, the yellow region (yolk) is the physicochemical area of molecules most likely to penetrate the brain while the white area corresponds to the physicochemical area of molecules most likely to be absorbed by the gastrointestinal tract. Yolk and white areas in the map are not mutually exclusive. Here, reference drugs were written in purple text, while blue was used for reference inhibitors.

Fig. 2

Average binding energies of 7 and 8 compound series against the target SARS-CoV-2 enzymes. Here, compound 7 series was presented with pink bars while compound 8 series was represented with blue bars.

Fig. 3

3D representations of the interactions of compounds 8b, 8c, 8d, 8 f, 8 g, 8 h, 8k, Remdesivir, and VIR250, and 3D superimposed representations of their binding sites on the dimeric PLpro target structure.

Fig. 4

The calculated RMSF values per-residue for dimeric PLpro enzymes in wt system and 8b/8c/8d/8 f/8 g/8 h/8k/Remdesivir/VIR2507-Protein complexes. 3D conformational structure of dimeric (Chain A + Chain C complex) and monomeric (only Chain A) PLpro protein. Chain A in a grey cartoon and Chain C in a yellow cartoon with some flexible residue region in different colours were represented.

Fig. 5

The calculated relative RMSF values per-residue for dimeric PLpro enzymes in Protein and 8b/8c/8d/8 f/8 g/8 h/8k/Remdesivir/VIR2507 complexes.

Fig. 6

Hot, un-hot residues on dimeric PLpro. Chain A in a grey cartoon and Chain C in a yellow cartoon with hot residues in red, un-hot residues in blue, and both hot and unhot residue in pink were represented.