Highly Transmissible and pathogenic coronavirus that emerged in late December of 2019 caused Severe acute respiratory syndrome (SARS-CoV-2), which challenged human health and public safety. Severity of the disease depends on the viral load and the type of mutation that occurred in the coronavirus. Nonstructural proteins like, Nsp1, Nsp3, Nsp12 and Nsp13 including other viral proteins plays important role during viral replication life cycle. Viral Replication initiated by hacking the host cellular mechanism either by synergy or by suppression using nucleocapsid proteins of the virus. Spike (S) protein of the SARS-CoV-2 uses angiotensin-converting enzyme II (ACE2) and TRMPSS as a cell entry. Once virus enters host cell, nucleocapsid proteins along with its genome is releases from endosomes into cytosol of the host cell. Ca2+/CaM (Calmodulin)/Calcineurin complex of the host cell plays important role during viral replication which is mediated by nucleocapsid proteins of the virus. Nsp1/Nsp3 nonstructural proteins triggers synergetic activity with CD147/CyPA/HSPG pathway and TRMP2/ADPr/Ca+2 mediated Ca2+/CaM (Calmodulin)/Calcineurin synthesis and free radicle generation in mitochondria leading to viral replication and severe chemokine activation pathways. Docking studies were carried out to inhibit Cyclophilin A and TRMP2 proteins as drug targets. Natural compounds like Withanolide A, Columbin, Cucurbitacin E, Boswellic acid along with Cyclosporines, Vitamin E and N-Acetyl cysteine (NAC) were selected as ligands to study docking studies. Withanolide A and Cyclosporines had shown good inhibition activity against Cyclophilin A, whereas Columbin, Boswellic acid, Cucurbitacin E, Vitamin E and N-Acetyl cysteine (NAC) had shown inhibitory activity against TRMP2. Thus, we suggest conducting further studies to conclude above pathways mechanism and inhibitory effect of natural compounds against the Nsp1/Nsp3 mediated pathways Invitro and In vivo.