This total leads to the formation of structural proteins assembled, packed and released in the host cells (Fehr and Perlman, 2015). deviation in these enzymes, specifically in S proteins at the genomic/proteomic level, affects pathogenesis. The structural variations are discussed in light of the failure of small molecule development in COVID-19 therapeutic strategies. We have performed in-depth sequence- and structure-based analyses of these proteins to get deeper insights into the mechanism of pathogenesis, structure-function relationships, and development of modern therapeutic approaches. Structural and functional consequences of the selected mutations on these proteins and their association with SARS-CoV-2 virulency and human health are discussed in detail in the light of our comparative genomics analysis. the S protein of the virus, which interacts with the ACE2 receptors around the host cells (Lan et?al., 2020). In this positive sense, a single-stranded RNA virus escapes the hosts innate and adaptive immune response, causing overproduction of cytokines leading to the formation of cytokine storm (Song et?al., 2020). Patients in serious conditions have shown an alleviated expression of IL-2, IL-7, IL-10, IP10, MIP1A, MCP1, G-CSF and TNF cytokines (Huang C. et?al., 2020). The death is mainly observed to be caused by pneumonia affecting the patients respiratory system (Xu et?al., 2020). Along with acute respiratory distress syndrome, COVID-19 causes the manifestation of acute heart injuries, heart failures, inflammation leading to sepsis and multi-organ dysfunction in individuals in chronic cases (Wang D. et?al., 2020). The virus was initially thought to spread through droplets of infected individuals sneezing or coughing; however, recent reports claim their airborne transmission (Zou et?al., 2020; Tang et?al., 2021). The virus possesses four structural proteins- spike (S) protein that helps in attachment of the virus to the host cells ACE-2 receptors (Kandeel et?al., 2018); membrane (M) protein typically involved in the formation of viral membrane for enclosing the mature virus particles (Neuman et?al., 2011); nucleocapsid (N) protein involved in the formation of a viral protein coat, i.e., N which surrounds the genetic material of the virus (Risco et?al., 1996); and envelope (E) protein which is involved in the formation of the envelope that assembles the virion particles (Ruch and Machamer, 2012). The following gene arrangement has been observed in SARS-CoV-2 structural Citalopram Hydrobromide analysis: 5′ untranslated region (UTR) [non-structural genes (ORF 1a/ORF1b replicase gene), structural genes (S, M, E, and N) and accessory genes (ORF 3, ORF 6, ORF 7a, ORF 7b, ORF 8, ORF 9b)] 3′ UTR (Song et?al., 2019; Asrani et?al., 2020). Replicase genes account for the synthesis of non-structural proteins Citalopram Hydrobromide (NSPs). Sixteen NSPs assist in the replication and packaging of the Mouse monoclonal to Rab10 virus (Naqvi et?al., 2020). Accessory proteins usually differ among the different strains of Coronaviruses (Li et?al., 2020). SARS-CoV-2 shares more than 80% genomic similarity to the previous SARS-CoV strain that caused an outbreak in 2003 (Asrani et?al., 2020; Malik, 2020). Thus, it is known to exhibit a similar replication process as observed in the previous cases. Now, different mutant strains of this virus have been identified from different parts of the world, such as B.1.1.7 variant of SARS-CoV-2 was originally acknowledged in United Kingdom (UK), B.1.351 variant from South Africa, B.1.1.28 variant from Brazil, Citalopram Hydrobromide B.1.36 variant, N440K and E484Q mutations from India however; all these variants have now been identified and cultured following their spread to different parts of the world (Tang J. W. et?al., 2020; Islam et?al., 2021; Planas et?al., 2021). Apart from these single-site mutations, few variants have been reported to have double and triple mutations. B.1.617, a double mutant variant that originated from a combination of previously identified Coronavirus variants L452R and E484Q, has been found to cause major deaths in certain parts of India (Cherian et?al., 2021). A triple mutant (B.1.618) strain was recently found to cause major outbreaks and deaths in the Bengal region in India, leading to the worst COVID-19 outbreak (Huh et?al., 2021). Since the mutation rate of SARS-CoV-2 is very high, it is important to identify the major sites in its genome that show potential in mutating further and posing a risk to humankind (Chen J. et?al., 2020). It is also necessary to identify the mutation types that have occurred predominately to understand the selection pressure on this novel coronavirus strain Citalopram Hydrobromide (Presti et?al., 2020). In this article, we have performed mutational analysis on different proteins specific to SARS-CoV-2. We have explored the structural and functional consequences of the selected mutations around the protein structures and their conversation with.