The novel SARS-CoV-2 is the etiological agent causing the Coronavirus disease 2019 (COVID-19), which continues to become an inevitable pandemic outbreak. Over a short span of time, the structures of therapeutic target proteins for SARS-CoV-2 were identified based on the homology modelled structure of similar SARS-CoV transmission of 2003. Since the onset of the disease, the research community has been looking for a potential drug lead. Out of all the known resolved structures related to SARS-CoV, Main protease (M pro ) is considered an attractive anti-viral drug target on the grounds of its role in viral replication and probable non-interactive competency to bind to any viral host protein. To the best of our knowledge, till date only one compound has been identified and tested in-vivo as a potent inhibitor of M pro protein, addressed as N3 (PubChem Compound CID: 6323191) and is known to bind irreversibly to M pro suppressing its activity. Using computational approach, we intend to identify a probable natural fungal metabolite to interact and inhibit M pro . After screening various small molecules for molecular docking and dynamics simulation, we propose Pyranonigrin A, a secondary fungal metabolite to possess potent inhibitory potential against the Main protease (M pro ) expressed in SARS-CoV-2 virus.

The non-structural protein (nsp)-3 of SARS-CoV2 coronavirus is sought to be an essential target protein which is also named as papain-like protease (PLpro). This protease cleaves the viral polyprotein, but importantly in human host it also removes ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from interferon responsive factor 3 (IRF3) protein which ultimately downregulates the production of type I interferon leading to weakening of immune response. GRL0617 is the most potent known inhibitor for PLpro that was initially developed for SARS outbreak of 2003. The PLpro of SARS-CoV and CoV2 share 83% sequence identity but interestingly have several identical conserved amino acids that suggests GRL0617 to be an effective inhibitor for PLpro of SARS-CoV2. GRL0617 is a naphthalene-based molecule and interacts with Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro). To identify PLpro inhibitors, we prepared a library of secondary metabolites from fungi with aromatic nature and docked them with PLpro of SARS-CoV and SARS-CoV2. We found six hits which interacts with Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro). More surprisingly the top hit, Fonsecin, has naphthalene moiety in its structure, which recruits Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro) and has binding energy at par with control (GRL0617). Molecular dynamics (MD) simulation showed Fonsecin to interact with Tyr268 of SARS-CoV2-PLpro more efficiently than control (GRL0617) and interacting with a greater number of amino acids in the binding cleft of PLpro. Graphic abstract

The novel SARS-CoV-2 is the etiological agent causing the Coronavirus disease 2019 (COVID-19), which continues to become an inevitable pandemic outbreak. Over a short span of time, the structures of therapeutic target proteins for SARS-CoV-2 were identified based on the homology modelled structure of similar virus, SARS-CoV that transmitted rapidly in 2003. Since the outset of the disease, the research community has been looking for a potential drug lead. Out of all the known resolved structures related to SARS-CoV-2; 3-chymotrypsin (3 C) like protease (3CL pro) is considered as an attractive anti-viral drug compound on the grounds of its role in viral replication and probable non-interactive competency to bind to any viral host protein. To the best of our knowledge, till date only one compound has been identified and tested in-vitro as a potent inhibitor of 3CL pro protein, addressed as N3 (PubChem Compound CID: 6323191) and is known to bind irreversibly to 3CL pro suppressing its activity. Using computational approach, we intend to identify a probable natural fungal metabolite to interact and inhibit 3CL pro. Here after performing docking and molecular dynamics of various small molecules derived as a secondary metabolite from fungi, we propose Flaviolin as potent inhibitor of 3CL pro of novel Coronavirus SARS-CoV-2.

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Emergence of vector borne diseases has continued to take toll on millions of lives since its inception. The use of insecticides began as vector control strategy in the early 1900’s but the menace of insects is still prevalent. Additionally, the inadequate use of organophosphates and carbamates which target acetylcholine esterase (AChE), are known to develop resistance amongst vectors of transmission and are toxic to humans. In this study, extensive computational screening was performed using homology modelling, molecular docking, molecular dynamics (MD) simulation and free energy change calculation, which highlighted curcumin as a lead molecule out of ~ 1700 phytochemicals against Culex pipiens AChE. In vivo larvicidal activity was carried out along with in vivo and in vitro AChE inhibition assay to determine the biochemical efficacy of curcumin. Our study reveals that curcumin induces mortality in Cx. pipiens at an early stage of its life cycle by AChE inhibition. This also underlines the use of curcumin as a coming-age natural product insecticide.