Design, synthesis and in silico studies of novel N-(2-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives targeting receptor-binding domain (RBD) of SARS-CoV-2 Spike Glycoprotein and evaluation as antimicrobial and antimalarial agents

Background: Pneumonia induced by a novel coronavirus (SARS-CoV-2) was named as coronavirus disease 2019 (COVID-19). The Receptor-binding domain (RBD) of SARS-CoV-2 Spike Glycoprotein, causes invasion of the virus into the host cell by attaching with human angiotensin-converting enzyme-2 (hACE-2) which leads to further infection. Objectives: The novel N-(2-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives were designed and synthesized to inhibit the RBD of SARS-CoV-2 Spike Glycoprotein by applying molecular docking tools. Methods: The synthesized products was characterized by Infrared Spectroscopy (IR), and 1H Nuclear Magnetic Resonance (NMR). Results: All the derivatives were found to have a very good binding affinity between -9 to -10.1 kcal/mol, better than the drugs which are under investigation for the treatment of SARS-CoV-2 infection. Compound F1 has formed 4 hydrogen bonds whereas, F4 and F10 formed two hydrogen bonds each with RBD of SARS-CoV-2 Spike Glycoprotein. All the derivatives were subjected to antimicrobial, antifungal, and antimalarial susceptibility. Conclusion: From the above-obtained results, we have concluded that novel N-(2-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives have excellent potential to inhibit the receptor-binding domain (RBD) of SARS-CoV-2 Spike Glycoprotein, which is now an attentive target in designing SARS-CoV-2 inhibitors. This scaffold can hold an effective interest in the development of inhibitors for SARS-CoV-2 in the future if drug repurposing fails to serve the purpose.

Download Full-text

Role of key point Mutations in Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666200804161650 ◽

2020 ◽

Vol 20 ◽

Author(s):

Bipin Singh

Keyword(s):

Receptor Binding ◽

Point Mutations ◽

Binding Domain ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Angiotensin Converting Enzyme 2 ◽

Recent Outbreak ◽

Novel Coronavirus ◽

Genomic Similarity

: The recent outbreak of novel coronavirus (SARS-CoV-2 or 2019-nCoV) and its worldwide spread is posing one of the major threats to human health and the world economy. It has been suggested that SARS-CoV-2 is similar to SARSCoV based on the comparison of the genome sequence. Despite the genomic similarity between SARS-CoV-2 and SARSCoV, the spike glycoprotein and receptor binding domain in SARS-CoV-2 shows the considerable difference compared to SARS-CoV, due to the presence of several point mutations. The analysis of receptor binding domain (RBD) from recently published 3D structures of spike glycoprotein of SARS-CoV-2 (Yan, R., et al. (2020); Wrapp, D., et al. (2020); Walls, A. C., et al. (2020)) highlights the contribution of a few key point mutations in RBD of spike glycoprotein and molecular basis of its efficient binding with human angiotensin-converting enzyme 2 (ACE2).

Download Full-text

Understanding the Role of Key Point Mutations in Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein

10.20944/preprints202003.0394.v1 ◽

2020 ◽

Author(s):

Bipin Singh

Keyword(s):

Receptor Binding ◽

3D Structure ◽

Point Mutations ◽

Binding Domain ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus ◽

Genomic Similarity

The recent outbreak of novel coronavirus (2019-nCoV or SARS-CoV-2) and its spread to the whole world is currently posing one of the major threat to human health and the world economy. It has been suggested that 2019-nCoV is similar to SARS-CoV based on the genome sequence comparison. Despite the genomic similarity between SARS-CoV and SARS-CoV-2, the spike glycoprotein and receptor binding domain in SARS-CoV-2 shows considerable difference compared to SARS-CoV, due to the presence of several point mutations. We analyzed the receptor binding domain (RBD) from recently published 3D structure of spike glycoprotein of SARS-CoV-2 and compared with RBD of SARS-CoV. The observations highlight few important features of RBD in the light of the recently published findings from the 3D structures of spike glycoprotein and its complex with human angiotensin-converting enzyme 2 (ACE2) (Yan, R., et al. (2020); Wrapp, D., et al. (2020); Walls, A. C., et al. (2020)).

Download Full-text

Understanding the Role of Key Point Mutations in Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein

10.20944/preprints202003.0394.v2 ◽

2020 ◽

Author(s):

Bipin Singh

Keyword(s):

Receptor Binding ◽

3D Structure ◽

Point Mutations ◽

Binding Domain ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus ◽

Genomic Similarity

The recent outbreak of novel coronavirus (SARS-CoV-2 or 2019-nCoV) and its spread to the whole world is currently posing one of the major threats to human health and the world economy. It has been suggested that SARS-CoV-2 is similar to SARS-CoV based on the genome sequence comparison. Despite the genomic similarity between SARS-CoV and SARS-CoV-2, the spike glycoprotein and receptor binding domain in SARS-CoV-2 shows considerable difference compared to SARS-CoV, due to the presence of several point mutations. We analyzed the receptor binding domain (RBD) from recently published 3D structure of spike glycoprotein of SARS-CoV-2 and compared with RBD of SARS-CoV. The observations highlight few important features of RBD in the light of the recently published findings from the 3D structures of spike glycoprotein and its complex with human angiotensin-converting enzyme 2 (ACE2) (Yan, R., et al. (2020); Wrapp, D., et al. (2020); Walls, A. C., et al. (2020)).

Download Full-text

Site-specific characterisation of SARS-CoV-2 spike glycoprotein receptor binding domain

Glycobiology ◽

10.1093/glycob/cwaa085 ◽

2020 ◽

Author(s):

Aristotelis Antonopoulos ◽

Steven Broome ◽

Victor Sharov ◽

Christopher Ziegenfuss ◽

Richard L Easton ◽

...

Keyword(s):

Receptor Binding ◽

Infection Process ◽

Binding Domain ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Analytical Strategy ◽

Site Specific ◽

Angiotensin Converting Enzyme 2 ◽

Binding Domains ◽

Novel Coronavirus

Abstract The novel coronavirus SARS-CoV-2, the infective agent causing COVID-19, is having a global impact both in terms of human disease as well as socially and economically. Its heavily glycosylated spike glycoprotein is fundamental for the infection process, via its receptor binding domains interaction with the glycoprotein angiotensin converting enzyme 2 on human cell surfaces. We therefore utilized an integrated glycomic and glycoproteomic analytical strategy to characterise both N- and O- glycan site specific glycosylation within the receptor binding domain. We demonstrate the presence of complex type N-glycans with unusual fucosylated LacdiNAc at both sites N331 and N343 and a single site of O-glycosylation on T323.

Download Full-text

Discovery of potential inhibitors of the receptor-binding domain (RBD) of pandemic disease-causing SARS-CoV-2 Spike Glycoprotein from Triphala through molecular docking

Current Chinese Chemistry ◽

10.2174/2666001601666210322121802 ◽

2021 ◽

Vol 01 ◽

Author(s):

Sharuk L. Khan ◽

Falak A. Siddiqui ◽

Mohd Sayeed Shaikh ◽

Nitin V. Nema ◽

Aijaz A. Shaikh

Keyword(s):

Molecular Docking ◽

Hydrogen Bonds ◽

Receptor Binding ◽

Chemical Constituents ◽

Antioxidant Properties ◽

Binding Domain ◽

Quality Data ◽

Receptor Binding Domain ◽

Spike Glycoprotein

Background: COVID-19 (SARS-CoV-2 infection) has affected almost every region of the world. Presently, there is no defined line of treatment available for it. Triphala is already proven to have a safe biological window and well known for its antioxidant and immunomodulatory properties. Objective: Present work has been carried out to study Triphala's effectiveness for the treatment of COVID-19. Methods: The Receptor-binding domain (RBD) of SARS-CoV-2 Spike Glycoprotein responsible for the invasion into the host cell, which leads to further infection. The molecular docking (MD) was performed to explore the binding affinities (kcal/mol) of Triphala's chemical constituents and compared them with the existing drugs under investigation for the treatment of COVID-19 epidemiology. Results: Chebulinic acid binding affinity -8.5 kcal/mol with the formation of 10 hydrogen bonds. Almost all the major chemical constituents have formed two or more hydrogen bonds with RBD of SARS-CoV-2 Spike Glycoprotein. Conclusion: The present study showed that Triphala might perform vital roles in the treatment of COVID-19 and expand its usefulness to physicians to treat this illness. There is a need to complete the in-vitro, in-vivo biological testing of Triphala on SARS-CoV-2 disease to create more quality data. The binding mode of Chebulinic acid in the allosteric cavity allows a better understanding of RBD of SARS-CoV-2 Spike Glycoprotein target and provides insight for the design of new inhibitors. Triphala is already proven to have a safe biological window, which indicates we can skip the pre-clinical trials. Apart from this, Triphala is well known for its antioxidant properties, which ultimately improves the immunity of the COVID-19 patient.

Download Full-text

Computational simulations reveal the binding dynamics between human ACE2 and the receptor binding domain of SARS-CoV-2 spike protein

10.1101/2020.03.24.005561 ◽

2020 ◽

Cited By ~ 9

Author(s):

Cecylia S. Lupala ◽

Xuanxuan Li ◽

Jian Lei ◽

Hong Chen ◽

Jianxun Qi ◽

...

Keyword(s):

Receptor Binding ◽

Genomic Analysis ◽

Md Simulations ◽

Binding Domain ◽

Spike Protein ◽

Receptor Binding Domain ◽

Binding Modes ◽

Angiotensin Converting Enzyme 2 ◽

Causal Pathogen ◽

Novel Coronavirus

AbstractA novel coronavirus (the SARS-CoV-2) has been identified in January 2020 as the causal pathogen for COVID-19 pneumonia, an outbreak started near the end of 2019 in Wuhan, China. The SARS-CoV-2 was found to be closely related to the SARS-CoV, based on the genomic analysis. The Angiotensin converting enzyme 2 protein (ACE2) utilized by the SARS-CoV as a receptor was found to facilitate the infection of SARS-CoV-2 as well, initiated by the binding of the spike protein to the human ACE2. Using homology modeling and molecular dynamics (MD) simulation methods, we report here the detailed structure of the ACE2 in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The predicted model is highly consistent with the experimentally determined complex structures. Plausible binding modes between human ACE2 and the RBD were revealed from all-atom MD simulations. The simulation data further revealed critical residues at the complex interface and provided more details about the interactions between the SARS-CoV-2 RBD and human ACE2. Two mutants mimicking rat ACE2 were modeled to study the mutation effects on RBD binding to ACE2. The simulations showed that the N-terminal helix and the K353 of the human ACE2 alter the binding modes of the CoV2-RBD to the ACE2.

Download Full-text

Molecular Docking study of Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein with Saikosaponin, a Triterpenoid Natural Product

10.26434/chemrxiv.12033774.v1 ◽

2020 ◽

Cited By ~ 2

Author(s):

Tamal Goswami ◽

Bhaskar Bagchi

Keyword(s):

Molecular Docking ◽

Receptor Binding ◽

Docking Study ◽

Binding Domain ◽

Target Cells ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Molecular Docking Study ◽

Computational Docking ◽

Angiotensin Converting Enzyme 2

The appearance of SARS-CoV-2 has resulted ~19000 deaths and ~423000 infections worldwide as of March 24, 2020. Coronavirus spike (S) glycoproteins hooks on target cells and binds to the angiotensin-converting enzyme 2 (ACE2) receptor. Recent researches speculated that residues 331 to 524 of the S glycoprotein of the receptor binding domain (RDB) of the spike is the most crucial target and this side was very important for computational docking. In the present study we have considered a series of saikosaponins and molecular docking was performed. Most of the docked molecules bind favorably to the RDB region of the spike glycoprotein and among them Saikosaponin B4 is the best inhibitor.

Download Full-text

Identification of a SARS-like bat coronavirus that shares structural features with the spike glycoprotein receptor-binding domain of SARS-CoV-2

Access Microbiology ◽

10.1099/acmi.0.000166 ◽

2020 ◽

Vol 2 (11) ◽

Author(s):

Conchita Fraguas Bringas ◽

David Booth

Keyword(s):

Receptor Binding ◽

Structural Features ◽

Binding Domain ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Angiotensin Converting Enzyme 2 ◽

Reliable Model ◽

High Conservation ◽

Host Range Determination ◽

Bat Coronavirus

SARS-CoV-2 is a recently emerged coronavirus that binds angiotensin-converting enzyme 2 (ACE2) for cell entry via its receptor-binding domain (RBD) on a surface-expressed spike glycoprotein. Studies show that despite its similarities to severe acute respiratory syndrome (SARS) coronavirus, there are critical differences in key RBD residues when compared to SARS-CoV-2. Here we present a short in silico study, showing that SARS-like bat coronavirus Rs3367 shares a high conservation with SARS-CoV-2 in important RBD residues for ACE2 binding: SARS-CoV-2’s Phe486, Thr500, Asn501 and Tyr505; implicated in receptor-binding strength and host-range determination. These features were not shared with other studied bat coronaviruses belonging to the betacoronavirus genus, including RaTG13, the closest reported bat coronavirus to SARS-CoV-2’s spike protein. Sequence and phylogeny analyses were followed by the computation of a reliable model of the RBD of SARS-like bat coronavirus Rs3367, which allowed structural insight of the conserved residues. Superimposition of this model on the SARS-CoV-2 ACE2-RBD complex revealed critical ACE2 contacts are also maintained. In addition, residue Asn488Rs3367 interacted with a previously defined pocket on ACE2 composed of Tyr41, Lys353 and Asp355. When compared to available SARS-CoV-2 crystal structure data, Asn501SARS-CoV-2 showed a different interaction with the ACE2 pocket. Taken together, this study offers molecular insights on RBD-receptor interactions with implications for vaccine design.

Download Full-text

SARS-CoV-2 Structural Analysis of Receptor Binding Domain New Variants from United Kingdom and South Africa

Research Ideas and Outcomes ◽

10.3897/rio.7.e62936 ◽

2021 ◽

Vol 7 ◽

Author(s):

Victor Padilla-Sanchez

Keyword(s):

South Africa ◽

United Kingdom ◽

Structural Analysis ◽

Receptor Binding ◽

Binding Domain ◽

The Other ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Spike Glycoprotein ◽

Angiotensin Converting Enzyme 2

SARS-CoV-2 has caused more than 80 million infections and close to 2 million deaths worldwide as of January 2021. This pandemic has caused an incredible damage to humanity being it medically and/or financially halting life as we know it. If it were not enough, the current virus is changing to a more deadly form because of the mutations that are arising on its genome. Importantly, two variants have emerged in recent months, one in United Kingdom and the other in South Africa that are more infectious and escape antibody binding. These two variants have mutations in the receptor binding domain of the spike glycoprotein namely N501Y (UK, SA), K417N (SA) and E484K (SA). Here, I present a structural analysis of spike glycoprotein bound to ACE2 (angiotensin converting enzyme 2) where the mutations have been introduced in silico showing the reason why these variants bind better to ACE2 receptors.

Download Full-text