Identification of therapeutic target in S2 domain of SARS nCov-2 Spike glycoprotein: Key to design and discover drug candidates for inhibition of viral entry into host cell

Abstract

Humanity is facing a grieve danger of coronavirus disease-19 caused by severe acute respiratory syndrome novel coronavirus-2 (SARS nCov-2). There is an urgent need of therapeutics that can help in overcoming this global pandemic. Identifying novel therapeutic target and screening already approved drug is a faster approach in this situation. Spike glycoprotein (Sgp) of SARS nCoV-2 is potentials target where in researchers have targeted receptor binding domain (RBD) of S1 domain. The S2 domain of Sgp also plays a pivotal role in viral entry, but the mechanism is less understood. We analyzed the structure of Sgp S2 domain in pre-fusion state and Heptad repeat region in its post-fusion state available from protein data bank. Sgp shows three major regions in S2 domain, the fusion peptide (FP), heptad repeat 1 (HR1) and central helical (CH) region. The HR1 region undergoes structural changes by flipping approximately 180∘ and coil up to form a rod like structure during fusion process implying its role in viral entry into the host cell. This structural change in S2 domain helices is crucial step, if this process is hindered by targeting the HR1 and CH region then the progression of virus can be stopped. Possible binding cavity was identified near the HR1 and CH region in S2 domain and docking-based virtual screening of FDA approved drugs was performed. Promising candidates like Troxerutin, Thymopentin and Daclatasvir can be used as therapeutics provided an immediate in-vitro and clinical studies are carried out by research groups.