The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach

AbstractThe novel coronavirus disease (COVID-19) is currently a big concern around the world. Recent reports show that the disease severity and mortality of COVID-19 infected patients may vary from gender to gender with a very high risk of death for seniors. In addition, some steroid structures have been reported to affect coronavirus, SARS-CoV-2, function and activity. The entry of SARS-CoV-2 into host cells depends on the binding of coronavirus spike protein to angiotensin converting enzyme-2 (ACE2). Viral main protease is essential for the replication of SARS-CoV-2. It was hypothesized that steroid molecules (e.g., estradiol, progesterone, testosterone, dexamethasone, hydrocortisone, prednisone and calcitriol) could occupy the active site of the protease and could alter the interaction of spike protein with ACE2. Computational data showed that estradiol interacted more strongly with the main protease active site. In the presence of calcitriol, the binding energy of the spike protein to ACE2 was increased, and transferring Apo to Locked S conformer of spike trimer was facilitated. Together, the interaction between spike protein and ACE2 can be disrupted by calcitriol. Potential use of estradiol and calcitriol to reduce virus invasion and replication needs clinical investigation.

Download Full-text

Computational Modeling Indicates A Decreased Affinity of SARS-CoV-2 to ACE2 by Steroids

10.21203/rs.3.rs-86139/v1 ◽

2020 ◽

Author(s):

Alireza Mansouri ◽

Rasoul Kowsar ◽

Khaled Sadeghi ◽

Akio Miyamoto

Keyword(s):

Binding Free Energy ◽

Spike Protein ◽

The Novel ◽

Angiotensin Converting Enzyme 2 ◽

Risk Of Death ◽

Main Protease ◽

The World ◽

Novel Coronavirus ◽

Very High ◽

Potential Use

Abstract The novel coronavirus disease (COVID-19) presently poses significant concerns around the world. Latest reports show that the degree of disease and mortality of COVID-19 infected patients may vary from gender to gender with a very high risk of death for seniors. It was hypothesized that sex steroid hormones estradiol (E2), progesterone (P4), testosterone (T), and dexamethasone (DEX) may change the interaction of coronavirus spike protein (CSP) with angiotensin converting enzyme-2 (ACE2). Data showed that E2 was more strongly to interact with the main protease of the coronavirus, while T had the lowest affinity for CSP. The binding energy of the CSP to ACE2 was increased in the presence of steroids; the greatest increase was observed by DEX and E2. The binding free energy of the CSP to ACE2 was the highest in the presence of E2 and DEX. Together, the interaction between CSP and ACE2 can be disrupted by E2 and to a greater extent by DEX, in part explaining the lower incidence of COVID-19 infection in women than men. The potential use of E2 and DEX to reduce coronavirus attachment to ACE2 in the early phase of the coronavirus invasion needs to be clinically investigated.

Download Full-text

ACE-2-derived Biomimetic Peptides for the Inhibition of Spike Protein of SARS-CoV-2

10.26434/chemrxiv.12335933.v1 ◽

2020 ◽

Author(s):

Saroj Kumar Panda ◽

Parth Sarthi Sen Gupta ◽

Satyaranjan Biswal ◽

Abhik Kumar Ray ◽

Malay Kumar Rana

Keyword(s):

Principal Component ◽

Host Cells ◽

Spike Protein ◽

Peptide Inhibitor ◽

The Novel ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Inhibition Assay ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus

<p>SARS-CoV-2, a novel coronavirus causing overwhelming death and infection worldwide, has emerged as a pandemic. Compared to its predecessor SARS-CoV, SARS-CoV-2 is more infective for being highly contagious and exhibiting tighter binding with host angiotensin-converting enzyme 2 (hACE-2). The entry of the virus into host cells is mediated by the interaction of its spike protein with hACE-2. Thus, a peptide that has a resemblance to hACE-2 but can overpower the spike protein-hACE-2 interaction will be a potential therapeutic to contain this virus. The non-interacting residues in the receptor-binding domain of hACE-2 have been mutated to generate a library of 136 new peptides. Out of this library, docking and virtual screening discover seven peptides that can exert a stronger interaction with the spike protein than hACE-2. A peptide derived from simultaneous mutation of all the non-interacting residues of hACE-2 yields two-fold stronger interaction than hACE-2 and thus turns out here to be the best peptide-inhibitor of the novel coronavirus. The binding of the spike protein and the best peptide-inhibitor with hACE-2 is explored further by molecular dynamics, free energy, and principal component analysis to demonstrate its efficacy. Further, the inhibition assay study with the best peptide inhibitor is in progress. </p>

Download Full-text

Impact of Thiol-Disulfide Balance on the Binding of Covid-19 Spike Protein with Angiotensin Converting Enzyme 2 Receptor

10.1101/2020.05.07.083147 ◽

2020 ◽

Cited By ~ 4

Author(s):

Sanchita Hati ◽

Sudeep Bhattacharyya

Keyword(s):

Angiotensin Converting Enzyme ◽

Binding Affinity ◽

Disulfide Bonds ◽

Host Cells ◽

Converting Enzyme ◽

Dynamic Simulations ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus ◽

The Impact ◽

Spike Proteins

AbstractThe novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease (COVID-19), which started in 2019. This is a member of Coronaviridae family in the genus Betacoronavirus, which also includes SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). The angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV and SARS-CoV-2 to enter the host cells. In particular, the interaction of viral spike proteins with ACE2 is a critical step in the viral replication cycle. The receptor binding domain of the viral spike proteins and ACE2 have several cysteine residues. In this study, the role of thiol-disulfide balance on the interactions between SARS-CoV/CoV-2 spike proteins and ACE2 was investigated using molecular dynamic simulations. The study revealed that the binding affinity was significantly impaired when all the disulfide bonds of both ACE2 and SARS-CoV/CoV-2 spike proteins were reduced to thiol groups. The impact on the binding affinity was less severe when the disulfide bridges of only one of the binding partners were reduced to thiols. This computational finding provides a molecular basis for the severity of COVID-19 infection due to the oxidative stress.

Download Full-text

Structural insights into decreased affinity of SARS-CoV-2 to ACE2 by steroids

10.21203/rs.3.rs-83198/v1 ◽

2020 ◽

Author(s):

Alireza Mansouri ◽

Rasoul Kowsar ◽

Khaled Sadeghi ◽

Akio Miyamoto

Keyword(s):

Steroid Hormones ◽

Binding Free Energy ◽

Sex Steroid Hormones ◽

Spike Protein ◽

Sex Steroid ◽

Sex Steroid Hormone ◽

Risk Of Death ◽

Main Protease ◽

Anti Inflammatory ◽

Novel Coronavirus

Abstract The novel coronavirus disease (COVID-19) presently poses significant concerns around the world. Latest reports show that the degree of disease and mortality of COVID-19 infected patients may vary from gender to gender with a very high risk of death for seniors. Clearly, different levels of sex steroid hormones are found in both men and women. It was hypothesized that sex steroid hormones estradiol (E2), progesterone (P4), and testosterone (T) may change the interaction of coronavirus spike protein with angiotensin converting enzyme-2 (ACE2, which is the major SARS-CoV-2 cell entry receptor.) in the presence or absence of dexamethasone (DEX, the potential anti-inflammatory agents). Data showed that E2 was more strongly to interact with the main protease of the coronavirus, while T had the lowest affinity for coronavirus spike protein than E2 and P4. The binding energy of the spike protein to ACE2 was increased in the presence of five molecules of each steroid; the greatest increase was observed by DEX and E2. The binding free energy of the spike protein to ACE2 was the highest in the presence of both E2 and DEX molecules. Together, the interaction between spike protein and ACE2 can be disrupted by female sex steroid hormone E2 and to a greater extent by E2 and anti-inflammatory DEX, in part explaining the lower incidence of COVID-19 infection in women than men. The potential use of E2 and DEX to reduce coronavirus attachment to ACE2 in the early phase of the coronavirus invasion needs to be clinically investigated.

Download Full-text

Carnosine to Combat Novel Coronavirus (nCoV): Molecular Docking and Modeling to Cocrystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein

Molecules ◽

10.3390/molecules25235605 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5605

Author(s):

Loai M. Saadah ◽

Ghina’a I. Abu Deiab ◽

Qosay Al-Balas ◽

Iman A. Basheti

Keyword(s):

Molecular Docking ◽

Angiotensin Converting Enzyme ◽

Active Site ◽

Host Cells ◽

Spike Protein ◽

Drug Candidate ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Experimental Drugs ◽

Starting Point

Aims: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. The current paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 cocrystallized with nCoV spike protein. Methods: First, the starting point was ACE2 inhibitors and their structure–activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. Parallel, at all stages, the authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 with nCoV spike protein. Results: Carnosine emerged as the best-known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the protein–protein structure, carnosine bound with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 and nCoV spike protein and hence could offer a potential mitigating effect against the current COVID-19 pandemic.

Download Full-text

Carnosine to Combat Novel Coronavirus (nCoV, COVID-19): Molecular Docking and Modeling to Co-Crystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein

10.20944/preprints202010.0486.v1 ◽

2020 ◽

Author(s):

Loai M. Saadah ◽

Ghina’a I Abu Deiab ◽

Qosay Al-Balas ◽

Iman A. Basheti

Keyword(s):

Molecular Docking ◽

Angiotensin Converting Enzyme ◽

Active Site ◽

Host Cells ◽

Spike Protein ◽

Drug Candidate ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Experimental Drugs ◽

Starting Point

Aims: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. This paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 co-crystallized with COVID-19 spike protein. Methods: First, the starting point was ACE2 inhibitors and their structure-activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. In parallel, at all stages, authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 co-crystallized with COVID-19 spike protein. Results: Carnosine emerged as the best known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the co-crystallized protein structure, carnosine bind with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 co-crystallized with COVID-19 spike protein and hence could offer potential mitigating effect against current COVID-19 pandemic.

Download Full-text

ACE-2-derived Biomimetic Peptides for the Inhibition of Spike Protein of SARS-CoV-2

10.26434/chemrxiv.12335933 ◽

2020 ◽

Author(s):

Saroj Kumar Panda ◽

Parth Sarthi Sen Gupta ◽

Satyaranjan Biswal ◽

Abhik Kumar Ray ◽

Malay Kumar Rana

Keyword(s):

Principal Component ◽

Host Cells ◽

Spike Protein ◽

Peptide Inhibitor ◽

The Novel ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Inhibition Assay ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus

Download Full-text

Blocking Effect of Demethylzeylasteral on the Interaction between Human ACE2 Protein and SARS-CoV-2 RBD Protein Discovered Using SPR Technology

Molecules ◽

10.3390/molecules26010057 ◽

2020 ◽

Vol 26 (1) ◽

pp. 57

Author(s):

Zhi-Ling Zhu ◽

Xiao-Dan Qiu ◽

Shuo Wu ◽

Yi-Tong Liu ◽

Ting Zhao ◽

...

Keyword(s):

Therapeutic Strategy ◽

Blocking Effect ◽

Spike Protein ◽

Binding Affinities ◽

The Novel ◽

Converting Enzyme ◽

Primary Method ◽

Angiotensin Converting Enzyme 2 ◽

Novel Coronavirus ◽

Effective Drugs

The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019, and there is no sign that the epidemic is abating. Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. In this study, surface plasmon resonance (SPR) was used as the primary method to screen a library of 960 compounds. A compound 02B05 (demethylzeylasteral, CAS number: 107316-88-1) that had high affinities for S-RBD and ACE2 was discovered, and binding affinities (KD, μM) of 02B05-ACE2 and 02B05-S-RBD were 1.736 and 1.039 μM, respectively. The results of a competition experiment showed that 02B05 could effectively block the binding of S-RBD to ACE2 protein. Furthermore, pseudovirus infection assay revealed that 02B05 could inhibit entry of SARS-CoV-2 pseudovirus into 293T cells to a certain extent at nontoxic concentration. The compoundobtained in this study serve as references for the design of drugs which have potential in the treatment of COVID-19 and can thus accelerate the process of developing effective drugs to treat SARS-CoV-2 infections.

Download Full-text

The Effects of Aβ1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2

International Journal of Molecular Sciences ◽

10.3390/ijms22158226 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8226

Author(s):

John Tsu-An Hsu ◽

Chih-Feng Tien ◽

Guann-Yi Yu ◽

Santai Shen ◽

Yi-Hsuan Lee ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Viral Entry ◽

Negative Impact ◽

Spike Protein ◽

Infection Model ◽

Converting Enzyme ◽

Viral Receptor ◽

Angiotensin Converting Enzyme 2 ◽

People With Dementia ◽

The Impact

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer’s disease (AD), the major form of dementia, β-amyloid (Aβ) levels in the blood are increased; however, the impact of elevated Aβ levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aβ1-42, but not Aβ1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aβ1-42. Furthermore, Aβ1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aβ1-42 show that the clearance of Aβ1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aβ antibody. In conclusion, these findings suggest that the binding of Aβ1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aβ1-42 in the blood is beneficial to the fight against COVID-19 and AD.

Download Full-text

Quinoline and Quinazoline Alkaloids against COVID-19: An In Silico Multitarget Approach

Journal of Chemistry ◽

10.1155/2021/3613268 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Esraa M. O. A. Ismail ◽

Shaza W. Shantier ◽

Mona S. Mohammed ◽

Hassan H. Musa ◽

Wadah Osman ◽

...

Keyword(s):

Antimalarial Activity ◽

The Novel ◽

Socioeconomic Impacts ◽

Health Crisis ◽

Natural Sources ◽

Angiotensin Converting Enzyme 2 ◽

Main Protease ◽

Recent Outbreak ◽

Novel Coronavirus ◽

Potential Inhibitors

The recent outbreak of the highly contagious coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 has created a global health crisis with socioeconomic impacts. Although, recently, vaccines have been approved for the prevention of COVID-19, there is still an urgent need for the discovery of more efficacious and safer drugs especially from natural sources. In this study, a number of quinoline and quinazoline alkaloids with antiviral and/or antimalarial activity were virtually screened against three potential targets for the development of drugs against COVID-19. Among seventy-one tested compounds, twenty-three were selected for molecular docking based on their pharmacokinetic and toxicity profiles. The results identified a number of potential inhibitors. Three of them, namely, norquinadoline A, deoxytryptoquivaline, and deoxynortryptoquivaline, showed strong binding to the three targets, SARS-CoV-2 main protease, spike glycoprotein, and human angiotensin-converting enzyme 2. These alkaloids therefore have promise for being further investigated as possible multitarget drugs against COVID-19.

Download Full-text