Identification of bio-active food compounds as potential SARS-CoV-2 PLpro inhibitors-modulators via negative image-based screening and computational simulations.

Despite significant studies on the COVID-19 pandemic, scientists around the world are still battling to find a definitive therapy against the ongoing severe global health crisis. In this study, advanced computational approaches have been employed to identify bioactive food constituents as potential SARS-CoV-2 PLpro inhibitors-modulators. As a validated antiviral drug target, PLpro has gained tremendous attention for therapeutics developments. Therefore, targeting the multifunctional SARS-CoV-2 PLpro protein, ∼1039 bioactive dietary compounds have been screened extensively through novel techniques like negative image-based (NIB) screening and molecular docking approaches. In particular, the three different models of NIB screening have been generated and used to re-score the dietary compounds based on the negative image which is created by reversing the shape and electrostatics features of PLpro protein's ligand-binding cavity. Further, 100 ns molecular dynamics simulation has been performed and MM-GBSA based binding free energies have been estimated for the final proposed four dietary compounds (PC000550, PC000361, PC000558, and PC000573) as potential inhibitors/modulators of SARS-CoV-2 PLpro protein. Employed computational study outcome also has been compared with respect to the earlier experimentally investigated compound GRL0617 against SARS-CoV-2 PLpro protein, which suggests much greater interaction potential in terms of binding affinity and other energetic contributions for the proposed dietary compounds. Hence, the present study suggests that proposed dietary compounds can be suitable chemical entities for modulating the activity of PLpro protein or can be further utilized for optimizing or screening of novel chemical surrogates, however also needs experimental evaluation for entry in clinical studies for better assessment.

Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches.

The current ongoing pandemic of COVID-19 urges immediate treatment measures for controlling the highly contagious SARS-CoV-2 infections. The papain-like protease (PLpro), which is released from nsp3, is presently being evaluated as a significant anti-viral drug target for COVID-19 therapy development. Particularly, PLpro is implicated in the cleavage of viral polyproteins and antagonizes the host innate immune response through its deubiquitinating and deISGylating actions, thus making it a high-profile antiviral therapeutic target. The present study reports a few specific food compounds that can bind tightly with the SARS-CoV-2 PLpro protein identified through extensive computational screening techniques. Precisely, extensive advanced computational approaches combining target-based virtual screening, particularly employing sub-structure based similarity search, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA based binding free energy calculations have been employed for the identification of the most promising food compounds with substantial functional implications as SARS-CoV-2 PLpro protein inhibitors/modulators. Observations from the present research investigation also provide a deeper understanding of the binding modes of the proposed four food compounds with SARS-CoV-2 PLpro protein. In docking analyses, all compounds have established essential inter-molecular interaction profiles at the active site cavity of the SARS-CoV-2 PLpro protein. Similarly, the long-range 100 ns conventional MD simulation studies also provided an in-depth understanding of probable interactions and dynamic behaviour of the SARS-CoV-2 PLpro protein-food compound complexes. Binding free energies of all molecular systems revealed a strong interaction affinity of food compounds towards the SARS-CoV-2 PLpro protein. Moreover, clear-cut comparative analyses against the known standard inhibitor also suggest that proposed food compounds may act as potential active chemical entities for modulating the action of the SARS-CoV-2 PLpro protein.

Structure-based identification of SARS-CoV-2 main protease inhibitors from anti-viral specific chemical libraries: an exhaustive computational screening approach.

Worldwide coronavirus disease 2019 (COVID-19) outbreak is still threatening global health since its outbreak first reported in the late 2019. The causative novel virus has been designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 emergent with significant mortality, there is no availability of definite treatment measures. It is now extremely desirable to identify potential chemical entities against SARS-CoV-2 for the treatment of COVID-19. In the present study, a state-of-art virtual screening protocol was implemented on three anti-viral specific chemical libraries against SARS-CoV-2 main protease (Mpro). Particularly, viewing the large-scale biological role of Mpro in the viral replication process it has been considered as a prospective anti-viral drug target. Herein, on collected 79,892 compounds, hierarchical multistep docking followed by relative binding free energy estimation has been performed. Thereafter, implying a user-defined XP-dock and MM-GBSA cut-off scores as -8.00 and -45.00 kcal/mol, chemical space has been further reduced. Exhaustive molecular binding interactions analyses and various pharmacokinetics profiles assessment suggested four compounds (ChemDiv_D658-0159, ChemDiv_F431-0433, Enamine_Z3019991843 and Asinex_LAS_51389260) as potent inhibitors/modulators of SARS-CoV-2 Mpro. In-depth protein-ligand interactions stability in the dynamic state has been evaluated by 100 ns molecular dynamics (MD) simulation studies along with MM-GBSA-based binding free energy estimations of entire simulation trajectories that have revealed strong binding affinity of all identified compounds towards Mpro. Hence, all four identified compounds might be considered as promising candidates for future drug development specifically targeting the SARS-CoV-2 Mpro; however, they also need experimental assessment for a better understanding of molecular interaction mechanisms.