In silico analysis of phytochemicals and non-phytochemicals and comparing their potentiality on inhibiting nsp12 and nsp14 in SARS-CoV-2 variants

The spread of SARS-CoV-2 and its variants, leads to global pandemic endangering human life and health. The primary challenge for the scientific community is to find a potential cure for the disease which can act on the emerging variants of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). Due to the absence of effective medical treatment for the diseases, the healthcare system around the world was at a standstill. The nsp12 and nsp14 are one of the important proteins which are involved in the replication and proofreading of SARS-CoV-2 respectively. Both the non-structural proteins have highly conserved regions and served as a popular target for corona virus inhibitors for drug screening. In this study, the primary aim is to find the potential inhibitors, both phytochemical and nonphytochemical, which could act on variants to inhibit the activity of nsp12 and nsp14. Also to compare the binding affinity of nsp12 and nsp14 with phytochemicals and nonphytochemicals. A combination of mutational landscape, structure-based virtual screening and molecular dynamics (MD) simulation approaches were utilized in this work. From the mutational landscape, two functionally active mutations were observed in nsp12 and single mutation was observed in nsp14 of SARS CoV-2 Variants. The molecular simulation is performed for drugs Cepharanthine (phytochemical) and Hypericin (phytochemical) with top binding affinity for nsp12 variants and for molecules Hypericin (phytochemical) and conivaptan (non-Phytochemical) having top binding affinity with nsp14 wildtype and variants.

In silico drug designing for coronaviral infection from natural compounds

Worldwide exposure to the Coronavirus has caused more than 6 billion fatalities since 2019. Corona is a typical RNA virus composed of glycoproteins (S), a small envelope (E), a membrane (M) and a Nucleocapsid protein (N). Genetic mutation of the virus highly influences virulence and increases the affinity of viral spike protein towards receptor (ACE2) by affecting the physiochemical properties and folding conformations. The scientific community has been attempting to forecast an appropriate potential inhibitor since the identification of viral infection. This study proposed to screen efficient inhibitors for corona among the natural compound repositories. We have retrieved 1,15,367 compounds from the IBS, NANPDB, TiPdb, NPASS and NUBBF DB databases. The compounds belonged to the native plants of Asia, Europe, America and Africa under various disciplines such as terpenoids, flavonoids, alkaloids, polyketides, lignans and steroids. Virtual screening is used to fix the potential inhibitor for coronaviral infection against the main protease activity. Corona viral Main Protease (1Q2W) structure was retrieved from the PDB and compounds prepared with Ligprep. Molecular docking aid to rank their binding energy based on interaction mechanism. Natural compounds with high affinity towards the main protease were subjected to MM-GBSA and Molecular dynamics for 100 ns.