Destabilizing the Structural Integrity of SARS-CoV2 Receptor Proteins by Curcumin Along with Hydroxychloroquine: An Insilco Approach for a Combination Therapy

2020 ◽  
Author(s):  
Akhileshwar Srivastava ◽  
Divya Singh
Keyword(s):  
Binding Energy ◽  
Combination Therapy ◽  
Receptor Binding ◽  
Structural Integrity ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Receptor Proteins ◽  
Main Protease ◽  
The Stability ◽  
Therapeutic Activities

Presently, an emerging disease (COVID-19) has been spreading across the world due to coronavirus (SARS-CoV2). For treatment of SARS-CoV2 infection, currently hydroxychloroquine has been suggested by researchers, but it has not been found enough effective against this virus. The present study based on in silico approaches was designed to enhance the therapeutic activities of hydroxychloroquine by using curcumin as an adjunct drug against SARS-CoV2 receptor proteins: main-protease and S1 receptor binding domain (RBD). The webserver (ANCHOR) showed the higher protein stability for both receptors with disordered score (<0.5). The molecular docking analysis revealed that the binding energy (-24.58 kcal/mol) of hydroxychloroquine was higher than curcumin (-20.47 kcal/mol) for receptor main-protease, whereas binding energy of curcumin (<a>-38.84</a> kcal/mol) had greater than hydroxychloroquine<a> (-35.87</a> kcal/mol) in case of S1 receptor binding domain. Therefore, this study suggested that the curcumin could be used as combination therapy along with hydroxychloroquine for disrupting the stability of SARS-CoV2 receptor proteins

Destabilizing the Structural Integrity of SARS-CoV2 Receptor Proteins by Curcumin Along with Hydroxychloroquine: An Insilco Approach for a Combination Therapy

2020 ◽  
Author(s):  
Akhileshwar Srivastava ◽  
Divya Singh
Keyword(s):  
Binding Energy ◽  
Combination Therapy ◽  
Receptor Binding ◽  
Structural Integrity ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Receptor Proteins ◽  
Main Protease ◽  
The Stability ◽  
Therapeutic Activities

Presently, an emerging disease (COVID-19) has been spreading across the world due to coronavirus (SARS-CoV2). For treatment of SARS-CoV2 infection, currently hydroxychloroquine has been suggested by researchers, but it has not been found enough effective against this virus. The present study based on in silico approaches was designed to enhance the therapeutic activities of hydroxychloroquine by using curcumin as an adjunct drug against SARS-CoV2 receptor proteins: main-protease and S1 receptor binding domain (RBD). The webserver (ANCHOR) showed the higher protein stability for both receptors with disordered score (<0.5). The molecular docking analysis revealed that the binding energy (-24.58 kcal/mol) of hydroxychloroquine was higher than curcumin (-20.47 kcal/mol) for receptor main-protease, whereas binding energy of curcumin (<a>-38.84</a> kcal/mol) had greater than hydroxychloroquine<a> (-35.87</a> kcal/mol) in case of S1 receptor binding domain. Therefore, this study suggested that the curcumin could be used as combination therapy along with hydroxychloroquine for disrupting the stability of SARS-CoV2 receptor proteins

scholarly journals Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain

2020 ◽  
Author(s):  
Mohamed Raef Smaoui ◽  
Hamdi Yahyaoui
Keyword(s):  
Receptor Binding ◽  
Single Point ◽  
Protein Structures ◽  
Point Mutations ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Point Mutant ◽  
The Stability ◽  
Spike Proteins

Abstract The interaction between the receptor-binding domain of the SARS-CoV-2 spike glycoprotein and the ACE2 enzyme is believed to be the entry point of the virus into various cells in the body, including the lungs, heart, liver, and kidneys. The current focus of several therapeutic design efforts explore attempts at affecting the binding interaction between the two proteins to limit the activity of the virus and disease progression. In this work, we analyze the stability of the spike protein under all possible single-point mutations in the receptor-binding domain and computationally explore mutations that can affect the binding with the ACE2 enzyme. We unravel the mutation landscape of the receptor region and assess the toxicity potential of single and multi-point mutations, generating insights for future vaccine efforts on potential mutations that might further stabilize the spike protein and increase its infectivity. We developed a tool, called SpikeMutator, to construct full atomic protein structures of the mutant spike proteins and shared a database of 3,800 single-point mutant structures. We analyzed the recent 65,000 reported spike sequences across the globe and observed the emergence of stable multi-point mutant structures. Using the landscape, we searched through 7.5 million possible 2-point mutation combinations and report that the (R355D K424E) mutation produces one of the strongest spike proteins that therapeutic efforts should investigate for the sake of developing an effective vaccine.

scholarly journals An exploration of the SARS-CoV-2 spike receptor binding domain (RBD) – a complex palette of evolutionary and structural features

2020 ◽  
Author(s):  
Dwipanjan Sanyal ◽  
Sourav Chowdhury ◽  
Vladimir N. Uversky ◽  
Krishnananda Chattopadhyay
Keyword(s):  
Receptor Binding ◽  
Sequence Space ◽  
Structural Integrity ◽  
Protein S ◽  
Structural Features ◽  
Binding Domain ◽  
Evolutionary Analysis ◽  
Receptor Binding Domain ◽  
Comprehensive Picture ◽  
Fuzzy C Means Clustering

AbstractSARS-CoV-2 spike protein (S) is associated with the entry of virus inside the host cell by recruiting its loop dominant receptor binding domain (RBD) and interacting with the host ACE2 receptor. Our study deploying a two-tier approach encompassing evolutionary and structural analysis provides a comprehensive picture of the RBD, which could be of potential use for better understanding the RBD and address its druggability issues. Resorting to an ensemble of sequence space exploratory tools including co-evolutionary analysis and deep mutational scans we provide a quantitative insight into the evolutionarily constrained subspace of the RBD sequence space. Guided by structure network analysis and Monte Carlo simulation we highlight regions inside the RBD, which are critical for providing structural integrity and conformational flexibility of the binding cleft. We further deployed fuzzy C-means clustering by plugging the evolutionary and structural features of discrete structure blocks of RBD to understand which structure blocks share maximum overlap based on their evolutionary and structural features. Deploying this multi-tier interlinked approach, which essentially distilled the evolutionary and structural features of RBD, we highlight discrete region, which could be a potential druggable pocket thereby destabilizing the structure and addressing evolutionary routes.

scholarly journals In Silico Evaluation of Iranian Medicinal Plant Phytoconstituents as Inhibitors against Main Protease and the Receptor-Binding Domain of SARS-CoV-2

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5724
Author(s):  
Seyyed Sasan Mousavi ◽  
Akbar Karami ◽  
Tahereh Movahhed Haghighi ◽  
Sefren Geiner Tumilaar ◽  
Fatimawali ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Medicinal Plants ◽  
Receptor Binding ◽  
Binding Free Energy ◽  
Binding Domain ◽  
Dynamics Simulation ◽  
Herbal Remedies ◽  
Receptor Binding Domain ◽  
Natural Origin ◽  
Main Protease

The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which initially appeared in Wuhan, China, in December 2019. Elderly individuals and those with comorbid conditions may be more vulnerable to this disease. Consequently, several research laboratories continue to focus on developing drugs to treat this infection because this disease has developed into a global pandemic with an extremely limited number of specific treatments available. Natural herbal remedies have long been used to treat illnesses in a variety of cultures. Modern medicine has achieved success due to the effectiveness of traditional medicines, which are derived from medicinal plants. The objective of this study was to determine whether components of natural origin from Iranian medicinal plants have an antiviral effect that can prevent humans from this coronavirus infection using the most reliable molecular docking method; in our case, we focused on the main protease (Mpro) and a receptor-binding domain (RBD). The results of molecular docking showed that among 169 molecules of natural origin from common Iranian medicinal plants, 20 molecules (chelidimerine, rutin, fumariline, catechin gallate, adlumidine, astragalin, somniferine, etc.) can be proposed as inhibitors against this coronavirus based on the binding free energy and type of interactions between these molecules and the studied proteins. Moreover, a molecular dynamics simulation study revealed that the chelidimerine–Mpro and somniferine–RBD complexes were stable for up to 50 ns below 0.5 nm. Our results provide valuable insights into this mechanism, which sheds light on future structure-based designs of high-potency inhibitors for SARS-CoV-2.

scholarly journals Insights into the Binding of Receptor-Binding Domain (RBD) of SARS-CoV-2 Wild Type and B.1.620 Variant with hACE2 Using Molecular Docking and Simulation Approaches

Biology ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1310
Author(s):  
Ziyad Tariq Muhseen ◽  
Salim Kadhim ◽  
Yahiya Ibrahim Yahiya ◽  
Eid A. Alatawi ◽  
Faris F. Aba Alkhayl ◽  
...  
Keyword(s):  
Binding Energy ◽  
Hydrogen Bonds ◽  
Receptor Binding ◽  
Salt Bridge ◽  
Binding Domain ◽  
Total Binding Energy ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Docking Score ◽  
Total Binding

Recently, a new variant, B.1620, with mutations (S477N-E484K) in the spike protein’s receptor-binding domain (RBD) has been reported in Europe. In order to design therapeutic strategies suitable for B.1.620, further studies are required. A detailed investigation of the structural features and variations caused by these substitutions, that is, a molecular level investigation, is essential to uncover the role of these changes. To determine whether and how the binding affinity of ACE2–RBD is affected, we used protein–protein docking and all-atom simulation approaches. Our analysis revealed that B.1.620 binds more strongly than the wild type and alters the hydrogen bonding network. The docking score for the wild type was reported to be −122.6 +/− 0.7 kcal/mol, while for B.1.620, the docking score was −124.9 +/− 3.8 kcal/mol. A comparative binding investigation showed that the wild-type complex has 11 hydrogen bonds and one salt bridge, while the B.1.620 complex has 14 hydrogen bonds and one salt bridge, among which most of the interactions are preserved between the wild type and B.1.620. A dynamic analysis of the two complexes revealed stable dynamics, which corroborated the global stability trend, compactness, and flexibility of the three essential loops, providing a better conformational optimization opportunity and binding. Furthermore, binding free energy revealed that the wild type had a total binding energy of −51.14 kcal/mol, while for B.1.628, the total binding energy was −68.25 kcal/mol. The current findings based on protein complex modeling and bio-simulation methods revealed the atomic features of the B.1.620 variant harboring S477N and E484K mutations in the RBD and the basis for infectivity. In conclusion, the current study presents distinguishing features of B.1.620, which can be used to design structure-based drugs against the B.1.620 variant.

scholarly journals Comparison of Clinically Approved Molecules on SARS-CoV-2 Drug Target Proteins: A Molecular Docking Study

2020 ◽  
Author(s):  
Hasan Cubuk ◽  
Mehmet Ozbil
Keyword(s):  
Molecular Docking ◽  
Drug Design ◽  
Receptor Binding ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Molecular Docking Study ◽  
Target Proteins ◽  
Docking Simulations ◽  
Main Protease

<p>The new type of coronavirus, SARS-CoV-2 has affected more than 6.3 million people worldwide. Since the first day the virus has been spotted in Wuhan, China, there are numerous drug design studies conducted all over the globe. Most of these studies target the receptor-binding domain of spike protein of SASR-CoV-2, which is known to bind human ACE2 receptor and SARS-CoV-2 main protease, vital for the virus’ replication. However, there might be a third target, human furin protease, which cleaves the virus’ S1-S2 domains taking active role in its entry into the host cell. In this study we docked five clinically used drug molecules, favipiravir, hydroxychloroquine, remdesivir, lopinavir, and ritonavir onto three target proteins, receptor binding domain of SARS-CoV-2 spike protein, SARS-CoV-2 main protease, and human furin protease. Results of molecular docking simulations revealed that human furin protease might be targeted against COVID-19. Remdesivir, a nucleic acid derivative, strongly bound to the active site of this protease, suggesting this molecule can be used as a template for designing novel furin protease inhibitorsto fight with the disease. Protein-drug interactions revealed at the molecular level in this study can pave the way for better drug design for each specific target.<br></p>

scholarly journals Comparison of Clinically Approved Molecules on SARS-CoV-2 Drug Target Proteins: A Molecular Docking Study

2020 ◽  
Author(s):  
Hasan Cubuk ◽  
Mehmet Ozbil
Keyword(s):  
Molecular Docking ◽  
Drug Design ◽  
Receptor Binding ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Molecular Docking Study ◽  
Target Proteins ◽  
Docking Simulations ◽  
Main Protease

<p>The new type of coronavirus, SARS-CoV-2 has affected more than 6.3 million people worldwide. Since the first day the virus has been spotted in Wuhan, China, there are numerous drug design studies conducted all over the globe. Most of these studies target the receptor-binding domain of spike protein of SASR-CoV-2, which is known to bind human ACE2 receptor and SARS-CoV-2 main protease, vital for the virus’ replication. However, there might be a third target, human furin protease, which cleaves the virus’ S1-S2 domains taking active role in its entry into the host cell. In this study we docked five clinically used drug molecules, favipiravir, hydroxychloroquine, remdesivir, lopinavir, and ritonavir onto three target proteins, receptor binding domain of SARS-CoV-2 spike protein, SARS-CoV-2 main protease, and human furin protease. Results of molecular docking simulations revealed that human furin protease might be targeted against COVID-19. Remdesivir, a nucleic acid derivative, strongly bound to the active site of this protease, suggesting this molecule can be used as a template for designing novel furin protease inhibitorsto fight with the disease. Protein-drug interactions revealed at the molecular level in this study can pave the way for better drug design for each specific target.<br></p>

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