New progresses on cell surface protein HSPA5/BiP/GRP78 in cancers and COVID-19.

Heat-shock-protein family A (Hsp70) member 5 (HSPA5), aliases GRP78 or BiP, is a protein encoded with 654 amino acids by the HSPA5 gene located on human chromosome 9q33.3. When the endoplasmic reticulum (ER) was stressed, HSPA5 translocated to the cell surface, the mitochondria, and the nucleus complexed with other proteins to execute its functions. On the cell surface, HSPA5/BiP/GRP78 can play diverse functional roles in cell viability, proliferation, apoptosis, attachments, and innate and adaptive immunity regulations, which lead to various diseases, including cancers and coronavirus disease 2019 (COVID-19). COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which caused the pandemic since the first outbreak in late December 2019. HSPA5, highly expressed in the malignant tumors, likely plays a critical role in SARS-CoV-2 invasion/attack in cancer patients via tumor tissues. In the current study, we review the newest research progresses on cell surface protein HSPA5 expressions, functions, and mechanisms for cancers and SARS-CoV-2 invasion. The therapeutic and prognostic significances and prospects in cancers and COVID-19 disease by targeting HSPA5 are also discussed. Targeting HSPA5 expression by natural products may imply the significance in clinical for both anti-COVID-19 and anti-cancers in the future.

How helpful were molecular dynamics simulations in shaping our understanding of SARS-CoV-2 spike protein dynamics?

The SARS-CoV-2 spike protein (S) represents an important viral component that is required for successful viral infection in humans owing to its essential role in recognition of and entry to host cells. The spike is also an appealing target for drug designers who develop vaccines and antivirals. This article is important as it summarizes how molecular simulations successfully shaped our understanding of spike conformational behavior and its role in viral infection. MD simulations found that the higher affinity of SARS-CoV-2-S to ACE2 is linked to its unique residues that add extra electrostatic and van der Waal interactions in comparison to the SARS-CoV S. This illustrates the spread potential of the pandemic SARS-CoV-2 relative to the epidemic SARS-CoV. Different mutations at the S-ACE2 interface, which is believed to increase the transmission of the new variants, affected the behavior and binding interactions in different simulations. The contributions of glycans to the opening of S were revealed via simulations. The immune evasion of S was linked to the spatial distribution of glycans. This help the virus to escape the immune system recognition. This article is important as it summarizes how molecular simulations successfully shaped our understanding of spike conformational behavior and its role in viral infection. This will pave the way to us preparing for the next pandemic as the computational tools are tailored to help fight new challenges.

In silico targeting of SARS-CoV-2 spike receptor-binding domain from different variants with chaga mushroom terpenoids.

Terpenoids from the chaga mushroom have been identified as potential antiviral agents against SARS-CoV-2. This is because it can firmly bind to the viral spike receptor binding domain (RBD) and the auxiliary host cell receptor glucose-regulated protein 78 (GRP78). The current work examines the association of the chaga mushroom terpenoids with the RBD of various SARS-CoV-2 variants, including alpha, beta, gamma, delta, and omicron. This association was compared to the SARS-CoV-2 wild-type (WT) RBD using molecular docking analysis and molecular dynamics modeling. The outcomes demonstrated that the mutant RBDs, which had marginally greater average binding affinities (better binding) than the WT, were successfully inhibited by the chaga mushroom terpenoids. The results suggest that the chaga mushroom can be effective against various SARS-CoV-2 variants by targeting both the host-cell surface receptor GRP78 and the viral spike RBD.Communicated by Ramaswamy H. Sarma.

Synthesis, Molecular Docking, c-Met inhibitions of 2,2,2-Trichloro-ethylidene-cyclohexane-1,3-dione Derivatives Together With Their Application as Target SARS-CoV-2 main Protease (Mpro) And as Potential Anti-Covid-19.

BACKGROUND: The lack of anti-COVID-19 treatment to date warrants urgent research into potential therapeutic targets. Virtual drug screening techniques enable the identification of novel compounds that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). OBJECTIVE: The binding of thehalogenated compounds to Mpro may inhibit the replication and transcription of SARS-CoV-2 and, ultimately, stop the virallife cycle. In times of dire need for anti-COVID-19 treatment, this study lays the ground work for further experimental research to investigate the efficacy and potential medical uses of these compounds to treat COVID-19. METHOD: New heterocyclic compounds were synthesized through the first reaction of cyclohexan-1,3-dione (1a) or dimedone (1b) with trichloroacetonitrile (2) to give the 2,2,2-trichloroethylidene)cyclohexane-1,3-dione derivatives 3a and 3b, respectively. The latter compounds underwent a series of heterocyclization reactions to produce biologically active compounds. RESULTS: Novel compounds including fused thiophene, pyrimidine and pyran derivatives were synthesized and tested against human RNA N7-MTase (hRNMT) and selected viral N7-MTases such as SARS-CoV nsp14 and Vaccinia D1-D12 complex to evaluate their specificity and their molecular modeling was also studied in the aim of producing anti covid-19 target molecules. CONCLUSION: The results showed that compounds 10a, 10b, 10c, 10e, 10f, 10g and 10h showed high % inhibitions against SARs-Covnsp 14. Whereas, compounds 5a, 7a, 8b, 10a, 10b, 10c and 10i showed high inhibitions against hRNMT. This study explored the binding affinity of twenty two halogenated compounds to the SARS-CoV-2 MPro and discovered fifteen compounds with higher binding affinity than Nelfinavir, of which three showed remarkable results. c-Met kinase inhibitions of 10a, 10f, 10g and 10h showed that all compounds exhibited higher inhibitions than the reference Foretinib.

Apoptose No Covid-19 Grave E Potenciais Biomarcadores Prognosticos

Objetivos: A COVID-19 apresenta alta taxa de infectividade e um amplo espectro clinico no qual, aproximadamente 3%-20% dos infectados necessitam de internacao hospitalar sendo destes, 10%-30% cuidados intensivos. A forma grave parece estar associada a um descontrole da resposta imune do hospedeiro, desta forma, a caracterizacao do perfil imune e fundamental para a definicao prognostica e terapeutica. Materiais e Metodos: Estudo prospectivo realizado de maio de 2020 a maio de 2021, recrutou adultos com COVID-19 grave internados em UTI, para a avaliacao de 17 citocinas. Foram realizadas coletas laboratoriais na admissao na UTI (D0) e apos, a cada 4 dias por no maximo, 20 dias. O grupo controle incluiu doadores de sangue voluntarios. O desfecho primario avaliado foi a sobrevida livre de Ventilacao Mecanica (VM). Este projeto foi aprovado pelo Comite de etica. Resultados: Nos 62 pacientes avaliados a idade mediana foi de 58,7 anos, houve uma predominancia no sexo masculino (74.2%), e alta prevalencia de comorbidades. A taxa de mortalidade foi de 8%, sendo 55% a necessidade de suporte ventilatorio invasivo. Dentre as citocinas avaliadas, se destacaram os niveis sericos elevados de Granzima B, Perforina e sFAS (FAS soluvel) nos doentes em relacao aos controles. Os valores medianos de Granzima B no D0 foram maiores quanto menor o tempo de sintomas. A avaliacao no D0 atraves da curva ROC, demonstrou um papel preditivo nos niveis de Perforina, Granzima B e sFAS para a evolucao para VM. Nao obstante, os niveis de sFAS no decorrer da internacao apresentaram correlacao direta com pior desfecho sendo um potencial marcador prognostico. Discussao: A apoptose ocorre atraves de 3 mecanismos: mediada por granulos (granzimas e perforinas);citotoxicidade atraves de Fas-FasL;e citotoxicidade atraves do ligante TRAIL. Maucourant et al. documentaram no diagnostico de COVID-19 grave, o aumento nos niveis de Perforina, representando a resposta celular NK. Alem disso, foi descrito que no decorrer da infeccao ha uma reducao da citotoxicidade NK, decorrente da exaustao imune. Em nossa amostra, os niveis no D0 destas 2 moleculas se relacionaram a gravidade, alem disso, foi possivel observar o aumento de Granzima B relacionado a precocidade dos sintomas, desta forma, indicando uma reducao evolutiva. O receptor FAS e seu Ligante (FASL), integrantes da familia TNF, sao responsaveis pela apoptose das celulas infectadas no inicio da infeccao e, mais tardio, dos linfocitos maduros auto-reativos. As formas soluveis dos receptores regulam de forma competitiva as suas particulas de membrana (inibicao). No entanto, sFAS e sFASL parecem ter papeis diferentes conforme a patologia e o momento da infeccao, podendo inibir seus receptores transmembrana ou desenvolver funcoes analogas. Andre et al. encontraram uma relacao direta dos niveis de sFASL no COVID-19 grave com Fas-FasL linfocitarios, a linfopenia e o pior prognostico. Sendo responsaveis, portanto, pela apoptose de linfocitos T ativados. Diante disso, avaliaram o uso de um inibidor de caspase-1 para bloquear o Fas, o qual aumentou a resposta antiviral. Conclusao: O sFAS e um potencial biomarcador para a avaliacao preditiva prognostica, desta forma, nossos dados sugerem que as vias da apoptose devem ser estudadas a fim de confirmar estes dados e ainda, explorar seu potencial como alvo terapeutico. Copyright © 2022

A Tempestade De Citocinas E O Desbalanco Imune No Covid-19 Grave

Objetivos: A infeccao pelo SARS-COV-2, responsavel pela COVID-19, se disseminou rapidamente. No final de 2019 a epidemia na China e, em marco de 2020, a pandemia mundial. Apresenta espectro clinico variavel, e em especial acomete o trato respiratorio. Os infectados podem ser assintomaticos ou ate evoluir com insuficiencia respiratoria aguda, disfuncao de multiplos orgaos e obito. Ha necessidade de internacao em 3%-20% e, destes, 10%-30% cuidados intensivos. Desta forma, ha uma preocupacao com a saturacao dos servicos de saude. A infeccao grave parece estar associada a um desequilibrio imune, desta forma, a melhor identificacao do perfil imune e fundamental para definicao prognostica e terapeutica. Materiais e Metodos: Avaliacao de adultos em UTI com COVID-19 grave, realizada de maio de 2020 a maio de 2021. Foram coletadas amostras de sangue total nas primeiras 24 horas de admissao (D0) na UTI e apos, a cada 4 dias por no maximo 20 dias. O grupo controle incluiu doadores de sangue voluntarios. Avaliamos 17 citocinas, dados clinicos e laboratoriais. O desfecho primario foi sobrevida livre de Ventilacao Mecanica (VM). Este projeto foi aprovado no Comite de etica em pesquisa. Resultados: Foram incluidos 62 pacientes com idade mediana de 58,7 anos e alta prevalencia de comorbidades. Observamos linfopenia associada a aumento na relacao neutrofilo-linfocito (NLR=9.8), niveis elevados de D-Dimero, DHL e PCR. A mortalidade foi de 8%, sendo necessario VM com uma mediana de 4 dias apos admissao UTI em 55%. A analise das citocinas no D0 em comparacao com o grupo controle evidenciou aumento nos niveis de sCD137, IL-10, Granzima-B, sFAS, IL-6, CCL-4, TNFalpha e perforina. Atraves da curva ROC foi possivel avaliar o papel preditivo para VM nos niveis de IL-6, TNFalpha, sCD137, sFAS, Perforina e Granzima-B. Discussao: O desequilibrio imune e o papel das citocinas vem sendo avaliado como fator causal da forma grave do COVID-19. A tempestade de citocinas e potencialmente fatal, uma doenca imune em que ha liberacao descontrolada destas celulas ativadas que desencadeia infiltrados celulares e liberacao de mediadores quimicos. E responsavel pela febre, fadiga e contribui tambem com extravasamento vascular, CIVD, disfuncao de multiplos orgaos, choque e obito. Em nosso estudo houve o aumento das citocinas IL-6, CCL4, TNFalpha, Granzima-B e perforina que sao marcadores pro inflamatorios, a IL-10 anti-inflamatoria e ainda, o sFAS e sCD137 responsaveis pela reducao da resposta celular T, por conseguinte, anti inflamatorios. Desta forma, representando a hiperativacao desequilibrada do sistema imune associada ao aumento de marcadores inflamatorios como D-Dimero e PCR. O aumento da NRL representa a gravidade da populacao, ja que estudos previos demonstraram como corte, acima de 3,63. O mecanismo de bloqueio imune atraves da ativacao de anti inflamatorios e apoptose de celulas auto reativas pode contribuir com o aumento de infeccoes secundarias tardias. O aumento das citocinas foi relacionado ao desfecho desfavoravel em diversos estudos, especialmente na manifestacao grave, sendo potenciais marcadores prognosticos. Conclusao: Nosso estudo ratifica a importancia das citocinas e o desequilibrio imune na forma grave do COVID-19. Alem disso, evidenciamos alguns potenciais marcadores preditivos de desfecho desfavoravel como TNFalpha, Perforina, Granzima-B, IL-6, sCD137 e sFAS. E ainda, estes podem ser estudados como potenciais alvos terapeuticos. Copyright © 2022

Synthesis and In Silico Study of Some New bis-[1,3,4]thiadiazolimines and bis-Thiazolimines as Potential Inhibitors for SARS-CoV-2 Main Protease.

A novel series of bis-[1,3,4]thiadiazolimines, and bis-thiazolimines, with alkyl linker, were synthesized through general routes from cyclization of 1,1'-(hexane-1,6-diyl)bis(3-phenylthiourea) and hydrazonoyl halides or α-haloketones, respectively. Docking studies were applied to test the binding affinity of the synthesized products against the Mpro of SARS-CoV-2. The best compound, 5h, has average binding energy (-7.50 ± 0.58 kcal/mol) better than that of the positive controls O6K and N3 (-7.36 ± 0.34 and -6.36 ± 0.31 kcal/mol). Additionally, the docking poses (H-bonds and hydrophobic contacts) of the tested compounds against the Mpro using the PLIP web server were analyzed.

SARS-CoV-2 Delta Variant is Recognized Through GRP78 Host-Cell Surface Receptor, In Silico Perspective.

Different SARS-CoV-2 new variants emerged and spread during the past few months, sparking infections and death counts. The new variant B.1.617 (delta variant) sparked in India in the past few months, causing the highest records. The B.1.617 variant of SARS-CoV-2 has the double mutations E484Q and L452R on its spike Receptor Binding Domain (RBD). The first mutation is like the reported South African and the Brazilian variants (501.V2 and B.1.1.248). This mutation lies in the region C480-C488, which we predicted before to be recognized by the host-cell receptor; Glucose Regulated Protein 78 (GRP78). In the current study, we test the binding affinity of the host-cell receptor GRP78 to the delta variant spike RBD using molecular docking and molecular dynamics simulations of up to 100 ns. Additionally, the ACE2-RBD is tested by protein-protein docking. The results reveal equal average binding affinities of the GRP78 against wildtype and delta variant spikes. This supports our previous predictions of the contribution of GRP78 in SARS-CoV-2 spike recognition as an auxiliary route for entry.

Targeting SARS-CoV-2 endoribonuclease: a structure-based virtual screening supported by in vitro analysis.

Researchers are focused on discovering compounds that can interfere with the COVID-19 life cycle. One of the important non-structural proteins is endoribonuclease since it is responsible for processing viral RNA to evade detection of the host defense system. This work investigates a hierarchical structure-based virtual screening approach targeting NSP15. Different filtering approaches to predict the interactions of the compounds have been included in this study. Using a deep learning technique, we screened 823,821 compounds from five different databases (ZINC15, NCI, Drug Bank, Maybridge, and NCI Diversity set III). Subsequently, two docking protocols (extra precision and induced fit) were used to assess the binding affinity of the compounds, followed by molecular dynamic simulation supported by the MM-GBSA free binding energy. Interestingly, one compound (ZINC000104379474) from the ZINC15 database has been found to have a good binding affinity of - 7.68 kcal/Mol. The VERO-E6 cell line was used to investigate its therapeutic effect in vitro. Half-maximal cytotoxic concentration and Inhibitory concentration 50 were determined to be 0.9 mg/ml and 0.01 mg/ml, respectively; therefore, the selectivity index is 90. In conclusion, ZINC000104379474 was shown to be a good hit for targeting the virus that needs further investigations in vivo to be a drug candidate.

Investigating the structure-activity relationship of marine polycyclic batzelladine alkaloids as promising inhibitors for SARS-CoV-2 main protease (Mpro).

Over a span of two years ago, since the emergence of the first case of the novel coronavirus (SARS-CoV-2) in China, the pandemic has crossed borders causing serious health emergencies, immense economic crisis and impacting the daily life worldwide. Despite the discovery of numerous forms of precautionary vaccines along with other recently approved orally available drugs, yet effective antiviral therapeutics are necessarily needed to hunt this virus and its variants. Historically, naturally occurring chemicals have always been considered the primary source of beneficial medications. Considering the SARS-CoV-2 main protease (Mpro) as the duplicate key element of the viral cycle and its main target, in this paper, an extensive virtual screening for a focused chemical library of 15 batzelladine marine alkaloids, was virtually examined against SARS-CoV-2 main protease (Mpro) using an integrated set of modern computational tools including molecular docking (MDock), molecule dynamic (MD) simulations and structure-activity relationships (SARs) as well. The molecular docking predictions had disclosed four promising compounds including batzelladines H-I (8-9) and batzelladines F-G (6-7), respectively according to their prominent ligand-protein energy scores and relevant binding affinities with the (Mpro) pocket residues. The best two chemical hits, batzelladines H-I (8-9) were further investigated thermodynamically though studying their MD simulations at 100 ns, where they showed excellent stability within the accommodated (Mpro) pocket. Moreover, SARs studies imply the crucial roles of the fused tricyclic guanidinic moieties, its degree of unsaturation, position of the N-OH functionality and the length of the side chain as a spacer linking between two active sites, which disclosed fundamental structural and pharmacophoric features for efficient protein-ligand interaction. Such interesting findings are greatly highlighting further in vitro/vivo examinations regarding those marine natural products (MNPs) and their synthetic equivalents as promising antivirals.

Dual targeting of RdRps of SARS-CoV-2 and the mucormycosis-causing fungus: an in silico perspective.

During the past few months, mucormycosis has been associated with SARS-CoV-2 infections. Molecular docking combined with molecular dynamics simulation is utilized to test nucleotide-based inhibitors against the RdRps of SARS-CoV-2 solved structure and Rhizopusoryzae RdRp model built in silico. The results reveal a comparable binding affinity of sofosbuvir, galidesivir, ribavirin and remdesivir compared with the physiological nucleotide triphosphates against R.oryzae RdRp as well as the SARS-CoV-2 RdRp as reported before. Additionally, other compounds such as setrobuvir, YAK, IDX-184 and modified GTP compounds 2, 3 and 4 show potential calculated average binding affinities against R. oryzae RdRp. The present in silico study suggests the dual inhibition potential of the recommended drugs and compounds against SARS-CoV-2 and R.oryzae RdRps.

Enhanced Compressed Maximal Frequent Patterns from COVID-19 Streaming Data

The Coronavirus disease (COVID-19) pandemic has led to a huge loss of human life. It has also severely affected the economic, social, and health systems around the world. Frequent pattern mining is one of the main research topics in data stream mining. It is significant in many critical applications, especially in the medical field. This paper proposes a Compressed Maximal Frequent Pattern based on a Damped Window model over a data stream (CMFP-DW). Its main contribution is to integrate the concept of correlation with the purpose of finding valuable patterns that are highly correlated. As such, a new type of pattern is defined, namely the correlated compressed maximal frequent pattern. The CMFP-DW approach is employed for mining accurate correlated maximal frequent patterns from streaming data, and it has been validated against a real-world COVID-19 dataset from the healthcare domain. Frequent patterns generated from this dataset are exploited with the purpose of detecting the COVID-19 cases in different countries of the world. This helps decision makers take the appropriate precautions to prevent the further spread of the COVID-19 pandemic across the world. The six experiments carried out show that the proposed approach outperforms two other existing approaches, namely the estDec and the CP-Tree algorithms regarding accuracy in extracting correlated maximal frequent patterns, memory usage, and the required response time.

Interference of Chaga mushroom terpenoids with the attachment of SARS-CoV-2; in silico perspective.

Finding a potent inhibitor to the pandemic SARS-CoV-2 is indispensable nowadays. Currently, in-silico methods work as expeditious investigators to screen drugs for possible repurposing or design new ones. Targeting one of the possible SARS-CoV-2 attachment and entry receptors, Glucose-regulated protein 78 (GRP78), is an approach of major interest. Recently, GRP78 was reported as a recognized representative in recognition of the latest variants of SARS-CoV-2. In this work, molecular docking and molecular dynamics simulations were performed on the host cell receptor GRP78. With its many terpenoid compounds, Chaga mushroom was tested as a potential therapeutic against the SARS-CoV-2 receptor, GRP78. Results revealed low binding energies (high affinities) toward the GRP78 substrate-binding domain ß (SBDß) of Chaga mushroom terpenoids. Even the highly specific cyclic peptide Pep42, which selectively targeted GRP78 over cancer cells in vivo, showed lower binding affinity against GRP78 SBDß compared to the binding affinities of terpenoids. These are auspicious results that need to be tested experimentally. Intriguingly, terpenoids work as a double sword as they can be used to interfere with VUI 202,012/01, 501.V2, and B.1.1.248 variants of SARS-CoV-2 spike recognition.

Multidimensional in silico strategy for identification of natural polyphenols-based SARS-CoV-2 main protease (Mpro) inhibitors to unveil a hope against COVID-19.

SARS-CoV-2, a rapidly spreading new strain of human coronavirus, has affected almost all the countries around the world. The lack of specific drugs against SARS-CoV-2 is a significant hurdle towards the successful treatment of COVID-19. Thus, there is an urgent need to boost up research for the development of effective therapeutics against COVID-19. In the current study, we investigated the efficacy of 81 medicinal plant-based bioactive compounds against SARS-CoV-2 Mpro by using various in silico techniques. The interaction affinities of polyphenolic compounds towards SARS-CoV-2 Mpro was assessed via intramolecular (by Quantum Mechanic), intermolecular (by Molecular Docking), and spatial (by Molecular Dynamic) simulations. Our obtained result demonstrate that Hesperidin, rutin, diosmin, and apiin are most effective compounds agents against SARS-CoV-2 Mpro as compared to Nelfinavir (positive control). This study will hopefully pave a way for advanced experimental research to evaluate the in vitro and in vivo efficacy of these compounds for the treatment of COVID-19.

Molecular dynamics simulations and MM-GBSA reveal novel guanosine derivatives against SARS-CoV-2 RNA dependent RNA polymerase.

According to the World Health Organization (WHO), SARS-CoV-2 is responsible for more than 5 M deaths and is reported in 223 countries infecting 250+ M people. Despite the current vaccination momentum, thousands of people die every day by COVID-19. Suggesting possible blockers of the viral RNA-dependent RNA polymerase is highly needed for potential effective therapeutics against SARS-CoV-2. This study utilizes combined molecular dynamics simulation and molecular docking to test novel guanosine derivatives against SARS-CoV-2 RdRp. Results reveal the binding potency of nineteen guanosine derivatives against SARS-CoV-2 solved structures. The bulky moieties (hydroxyl or fluorated phenyl moieties) added to the 2' position of the ribose ring positively impacted the binding affinity to RdRp. The current in silico study represents a one-step-ahead for suggesting new possible blockers of SARS-CoV-2 RdRp that are yet to be verified in the wet lab. It offers new potential binders or blockers of RdRp that bind to the protein active site tighter than remdesivir. The latter was approved by the food and drug administration (FDA) for emergency use against COVID-19 last year.

Targeting SARS-CoV-2 nonstructural protein 15 endoribonuclease: an in silico perspective.

The newly emerged human coronavirus, SARS-CoV-2, had begun to spread last year and sparked worldwide. In this study, molecular docking is utilized to test some previously approved drugs against the SARS-CoV-2 nonstructural protein 15 (Nsp15). We screened 23 drugs, from which three (saquinavir, valrubicin and aprepitant) show a paramount predicted binding affinity (-9.1, -9.6 and -9.2 kcal/mol, respectively) against SARS-CoV-2 Nsp15. Moreover, saquinavir and aprepitant make nonbonded interactions with Leu201 in the active site cavity of Nsp15, while the drug valrubicin interacts with Arg199 and Leu201. This binding pattern may be effective against the targeted protein, leading to Nsp15 blockage and virus abolition. Additionally, the pharmacological properties of the screened drugs are known since they have been approved against different viruses.

A Review of Human Coronaviruses' Receptors: The Host-Cell Targets for the Crown Bearing Viruses.

A novel human coronavirus prompted considerable worry at the end of the year 2019. Now, it represents a significant global health and economic burden. The newly emerged coronavirus disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the primary reason for the COVID-19 global pandemic. According to recent global figures, COVID-19 has caused approximately 243.3 million illnesses and 4.9 million deaths. Several human cell receptors are involved in the virus identification of the host cells and entering them. Hence, understanding how the virus binds to host-cell receptors is crucial for developing antiviral treatments and vaccines. The current work aimed to determine the multiple host-cell receptors that bind with SARS-CoV-2 and other human coronaviruses for the purpose of cell entry. Extensive research is needed using neutralizing antibodies, natural chemicals, and therapeutic peptides to target those host-cell receptors in extremely susceptible individuals. More research is needed to map SARS-CoV-2 cell entry pathways in order to identify potential viral inhibitors.