Highlights Screening more than fifty natural products for the SARS CoV-2 M pro protein target The compounds with higher hydrophobicity and lower flexibility can be more favorable inhibitor Terpenoid from marine sponge Cacospongia mycofijiensis shows excellent SARS CoV-2 M pro inhibitory activity In the point of binding affinity, bioavailability, pharmacokinetics and toxicity, the natural product can act as a potential drug candidate against COVID-19 virus.

All the plants and their secondary metabolites used in the present study were obtained from Ayurveda, with historical roots in the Indian subcontinent. The selected secondary metabolites have been experimentally validated and reported as potent antiviral agents against genetically-close human viruses. The plants have also been used as a folk medicine to treat cold, cough, asthma, bronchitis, and severe acute respiratory syndrome in India and across the globe since time immemorial. The present study aimed to assess the repurposing possibility of potent antiviral compounds with SARS-CoV-2 target proteins and also with host-specific receptor and activator protease that facilitates the viral entry into the host body. Molecular docking (MDc) was performed to study molecular affinities of antiviral compounds with aforesaid target proteins. The top-scoring conformations identified through docking analysis were further validated by 100 ns molecular dynamic (MD) simulation run. The stability of the conformation was studied in detail by investigating the binding free energy using MM-PBSA method. Finally, the binding affinities of all the compounds were also compared with a reference ligand, remdesivir, against the target protein RdRp. Additionally, pharmacophore features, 3D structure alignment of potent compounds and Bayesian machine learning model were also used to support the MDc and MD simulation. Overall, the study emphasized that curcumin possesses a strong binding ability with host-specific receptors, furin and ACE2. In contrast, gingerol has shown strong interactions with spike protein, and RdRp and quercetin with main protease (M pro ) of SARS-CoV-2. In fact, all these target proteins play an essential role in mediating viral replication, and therefore, compounds targeting aforesaid target proteins are expected to block the viral replication and transcription. Overall, gingerol, curcumin and quercetin own multitarget binding ability that can be used alone or in combination to enhance therapeutic efficacy against COVID-19. The obtained results encourage further in vitro and in vivo investigations and also support the traditional use of antiviral plants preventively.

A crucial virulence factor for intracellular Mycobacterium tuberculosis survival is Protein kinase G (PknG), a eukaryotic-like serinethreonine protein kinase expressed by pathogenic mycobacteria that blocks the intracellular degradation of mycobacteria in lysosomes. Inhibition of PknG results in mycobacterial transfer to lysosomes. Withania somnifera, a reputed herb in ayurvedic medicine, comprises a large number of steroidal lactones known as withanolides which show various pharmacological activities. We describe the docking of 26 withanferin and 14 withanolides from Withania somnifera into the three dimensional structure of PknG of M. tuberculosis using GLIDE. The inhibitor binding positions and affinity were evaluated using scoring functions- Glidescore. The withanolide E, F and D and Withaferin - diacetate 2 phenoxy ethyl carbonate were identified as potential inhibitors of PknG. The available drug molecules and the ligand AX20017 showed hydrogen bond interaction with the aminoacid residues Glu233 and Val235. In addition to Val235 the other amino acids, Gly237, Gln238 and Ser239 are important for withanolide inhibitor recognition via hydrogen bonding mechanisms.

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8 9Influenza viruses that infect humans are known to swiftly evolve over time. Influenza A virus 10 11 has a negative single-stranded RNA genome in eight segments. Pangenome analysis of twelve 12 13 strains of Influenza A viruses H1N1, H1N2, H2N2, H3N2, H5N1, H5N6, H7N2, H7N3, H7N7, 14 15 H7N9, H9N2, and H10N8 gave insight on the core genes that are conserved and accessory genes 16 that are specific for the strains. The proteins Neuraminidase, Matrix M1 and Nonstructural protein 17 1 were encoded by the core genes of segments 6, 7, and 8 respectively which proves that 20 they are conserved in almost all the strains of influenza. The 3Dimensional structures of the core 21 22 genes were interpreted by homology modeling and compared with corresponding Protein Data 23 24 Bank structures (4MWQ, IEA3, 2GX9). Among several anti-viral phytocompounds that were 25 26 virtually screened against the modeled and PDB target proteins, three molecules of Indian plant 27 Glycyrrhiza glabra had high scores and interactions. Compounds 2,4,4' Trihydrochalcone, 29 Davidigenin and Licoflavone B docked well with the Neuraminidase, Matrix protein M1 and 31 Nonstructural Protein NS1 respectively with good scores, minimized energy and interacted with 32 33 the active sites. The compounds obeyed Lipinski's Rule of five and exhibited drugability as well. 34 35Thus the present study focused on the drugable lead compounds from glabra that has inhibitory 36 37 activities against the viral attachment, replication and matrix structure.