ABSTRACT
Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has infected millions worldwide. SARS-CoV-2 spike protein uses Angiotensin-converting enzyme 2 (ACE2) and Transmembrane serine protease 2 (TMPRSS2) for entering and fusing the host cell membrane. However, interaction with spike protein receptors and protease processing are not the only factors determining coronaviruses' entry. Several proteases mediate the entry of SARS-CoV-2 virus into the host cell. Identifying receptor factors helps understand tropism, transmission, and pathogenesis of COVID-19 infection in humans. The paper aims to identify novel viral receptor or membrane proteins that are transcriptionally and biologically similar to ACE2 and TMPRSS2 through a fuzzy clustering technique that employs the Grey wolf optimizer (GWO) algorithm for finding the optimal cluster center. The exploratory and exploitation capability of GWO algorithm is improved by hybridizing mutation and crossover operators of the evolutionary algorithm. Also, the genetic diversity of the grey wolf population is enhanced by eliminating weak individuals from the population. The proposed clustering algorithm's effectiveness is shown by detecting novel viral receptors and membrane proteins associated with the pathogenesis of SARS-CoV-2 infection. The expression profiles of ACE2 protein and its co-receptor factor are analyzed and compared with single-cell transcriptomics profiling using the Seurat R toolkit, mass spectrometry (MS), and immunohistochemistry (IHC). Our advanced clustering method infers that cell that expresses high ACE2 level are more affected by SARS-CoV-infection. So, SARS-CoV-2 virus affects lung, intestine, testis, heart, kidney, and liver more severely than brain, bone marrow, skin, spleen, etc. We have identified 58 novel viral receptors and 816 membrane proteins, and their role in the pathogenicity mechanism of SARS-CoV-2 infection has been studied. Besides, our study confirmed that Neuropilins (NRP1), G protein-coupled receptor 78 (GPR78), C-type lectin domain family 4 member M (CLEC4M), Kringle containing transmembrane protein 1 (KREMEN1), Asialoglycoprotein receptor 1 (ASGR1), A Disintegrin and metalloprotease 17 (ADAM17), Furin, Neuregulin-1,(NRG1), Basigin or CD147 and Poliovirus receptor (PVR) are the potential co-receptors of SARS-CoV-2 virus. A significant finding is that heparin derivative glycosaminoglycans could block the replication of SARS-CoV-2 virus inside the host cytoplasm. The membrane protein N-Deacetylase/N-Sulfotransferase-2 (NDST2), Extostosin protein (EXT1, EXT2, and EXT3), Glucuronic acid epimerase (GLCE), and Xylosyltransferase I, II (XYLT1, XYLT2) could act as the therapeutic target for inhibiting the spread of SARS-CoV-2 infection. Drugs such as carboplatin and gemcitabine are effective in such situations.