Pharmacotherapeutic Potential of Natural Products to Target the SARS-CoV-2 PLpro Using Molecular Screening and Simulation Approaches

Abstract

Because of the essential role of PLpro in the regulation of replication and dysregulation of the host immune sensing, it is considered a therapeutic target for novel drug development.To reduce the risk of immune evasion and vaccine effectiveness, small molecular therapeutics are the best complementary approach. Hence, we used a structure-based drug-designing approach to identify potential small molecular inhibitors for PLpro of SARS-CoV-2. Initial scoring and re-scoring of the best hits revealed that three compounds NPC320891 (2,2-Dihydroxyindene-1,3-Dione), NPC474594 (Isonarciclasine), and NPC474595 (7-Deoxyisonarciclasine) exhibit higher docking scores than the control GRL0617. Investigation of the binding modes revealed that alongside the essential contacts, i.e., Asp164, Glu167, Tyr264, and Gln269, these molecules also target Lys157 and Tyr268 residues in the active site. Moreover, molecular simulation demonstrated that the reported top hits also possess stable dynamics and structural packing. Furthermore, the residues' flexibility revealed that all the complexes demonstrated higher flexibility in the regions 120-140, 160-180, and 205-215. The 120-140 and 160-180 lie in the finger region of PLpro, which may open/close during the simulation to cover the active site and push the ligand inside. In addition, the total binding free energy was reported to be − 32.65 ± 0.17 kcal/mol for the GRL0617-PLpro, for the NPC320891-PLpro complex, the TBE was − 35.58 ± 0.14 kcal/ mol, for the NPC474594-PLpro, the TBE was − 43.72 ± 0.22 kcal/mol, while for NPC474595-PLpro complex, the TBE was calculated to be − 41.61 ± 0.20 kcal/mol, respectively. Clustering of the protein's motion and FEL further revealed that in NPC474594 and NPC474595 complexes, the drug was seen to have moved inside the binding cavity along with the loop in the palm region harboring the catalytic triad, thus justifying the higher binding of these two molecules particularly. In conclusion, the overall results reflect favorable binding of the identified hits strongly than the control drug, thus demanding in vitro and in vivo validation for clinical purposes.

Elucidating the binding mechanism of SARS-CoV-2 NSP6-TBK1 and structure-based designing of phytocompounds inhibitors for instigating the host immune response

“…Significant efforts are underway to identify a potential molecular drug to combat the virus ( Martin and Cheng, 2022 ). Recently, multiple regions have reported the presence of novel strains of the virus which are demonstrating heightened transmissibility and virulence ( Gorbalenya et al, 2020 ; Harrison et al, 2020 ; Suleman et al, 2023a ; Sayaf et al, 2023 ). These emerging variants exhibit increased infectivity, spread more readily, and lead to more severe illness.…”

“…In severe cases, the virus can significantly impair lung function and even lead to fatalities ( Wu and McGoogan, 2020 ; Zhou et al, 2020 ). Recently, there have been reports of new strains of the virus in various regions of the world, which are showing increased transmissibility and virulence ( Gorbalenya et al, 2020 ; Harrison et al, 2020 ; Suleman et al, 2023a ; Sayaf et al, 2023 ). These emerging variants are more infectious, spread more easily, and cause more severe illness.…”

Exploring the natural products chemical space to abrogate the F3L-dsRNA interface of monkeypox virus to enhance the immune responses using molecular screening and free energy calculations

“…The aim is to disrupt its binding with double-stranded RNA (dsRNA) and mitigate the heightened infectivity of the monkeypox virus. Prior to the database screening, we applied Lipinski’s rule of five to exclude drug-like molecules, a criterion utilized in numerous studies ( Sayaf et al, 2023 ). The computational drug screening was performed using AutoDock Vina, targeting the F3L protein of the monkeypox virus.…”

Development of Fluorescence-Based Assays for Key Viral Proteins in the SARS-CoV-2 Infection Process and Lifecycle

“…The PLpro enzyme cleaves the viral poly-proteins, resulting in the liberation of nsp1, nsp2, and nsp3. This step is crucial for the replication of the virus [ 57 , 58 , 59 ].…”