Efficacy of Tinospora cordifolia in treating SARS‐CoV‐2: in silico studies

Introduction SARS‐CoV‐2 has struck as a major global pandemic causing COVID19 with acute respiratory distress syndrome (ARDS) and other respiratory diseases gradually affecting multiple organs. Currently, SARS‐CoV‐2 is affecting over 85.1 million global cases of SARS‐CoV‐2 (20.7 millions in US) infections with 1.84 million (0.352 million in US) deaths globally. SARS‐CoV‐2 genome is 30kb in size and makes 29 proteins including key Spike protein (SP) and RNA dependent RNA polymerase (RdRP). The SP facilitates the entry of the virus into human host cells. Interactions of potential drugs with the SP can prevent or inhibit the entry of the virus into the host cells by blocking the interaction. Similarly, the non‐structural proteins (nsp) 7 and 8 facilitate the function of the RdRp/nsp12 that is essential for the replication of viral genome leading to multiply and spread of the virus within and from the host. In this study, we have selected 26 known phytochemicals (TC1 ‐ TC26) from medicinally important Ayurvedic plant, Tinospora cordifolia (TC) , to study the interactions of these phytochemicals with key SARS‐CoV‐2 proteins using in silico methods. We have identified promising interactions between TC phytochemicals, and the key SARS‐CoV2 proteins that can potentially block the viral entry and/or replication of SARS‐CoV‐2 thereby preventing and treating COVID19. Methods A molecular docking algorithm, PatchDock, was used to study the interactions between target proteins and phytochemicals of TC. To filter out the redundant docking predictions resulting from the patch matching system, a RMSD clustering calculation is used. The molecular display program, Chimera, was used to display the interactions between the phytochemicals and SARS‐CoV‐2 viral proteins. Results Of the 26 compounds tested (TC1 ‐ TC26), 11 showed effective binding to inhibit the SARS‐CoV‐2 proteins, SP or nsp7/8/12 complex including RdRp. The effectiveness of the docking compounds was measured in terms of atomic contact energy (ACE) Scores and rankings based on clusters. The compounds TC1, TC4, TC10 and TC14 achieved lower scores (of binding) less than ‐100 showing potential binding to all three viral proteins/complexes, SP, RdRp and nsp7/8/12. Further, analysis indicates that TC4 and TC10 are binding remarkably close to the active site of the SP that binds to the ACE2 receptor of host cells, providing evidence for effective inhibition of the SP. TC1 and TC14 binds between the N‐terminal, palm domain, and thumb domain of the RdRp, creating an interaction inside the active site, substantially inhibiting its critical replication function. Conclusion For the first time, we present in silico evidence that TC4 and TC10, and TC1 and TC14 potentially impair the entry and replication of SARS‐COV‐2 proteins respectively by inhibiting the functions of Spike and RdRp/nsp7‐8/12 proteins respectively.