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An in silico LLPS perturbation approach in the design of a novel SARS-CoV-2 spike receptor-binding domain inhibitor

ABSTRACT: The reversible process where a homogenous fluid de-mixes into two distinctively separate liquid phases is referred to as LLPS (Liquid-liquid phase separation). The resulting liquid is made up of one dilute phase and one condensed phase. An increasing number of studies have shown that the liquid-liquid phase separation is an important principle that underlies intracellular organization in biological systems, forming liquid condensates without a membrane envelope, otherwise known as MLOs (membraneless organelles). Such organelles include the P bodies, nucleolus and stress granules. Moreover, the regulation of many other biological processes such as signal transduction, chromatin rearrangement and RNA metabolism have been linked to the liquid-liquid phase separation.

SUBMITTER: Durojaye O

PROVIDER: S-EPMC7685779 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Binder design for targeting SARS-CoV-2 spike protein: An in silico perspective.

Project description:IntroductionThe COVID-19 pandemic is now affecting all people around the world and getting worse. New antiviral medications are desperately needed other than the few approved medications that have shown no promising efficacy so far.MethodsHere we report three blocking binders for targeting SARS-CoV-2 spike protein to block the interaction between the spike protein on the SARS-CoV-2 and the angiotensin-converting enzyme 2 (ACE2) receptors, responsible for viral homing into the alveolar epithelium type II cells (AECII).ResultsThe design process is based on the collected natural scaffolds and using Rosetta interface for designing the binders.ConclusionBased on the structural analysis, three binders were selected, and the results showed that they might be promising as new therapeutic targets for blocking COVID-19.

| S-EPMC8616691 | biostudies-literature

Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike.

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| S-SCDT-EMBOR-2021-54322V1 | biostudies-other

In silico design of antiviral peptides targeting the spike protein of SARS-CoV-2.

Project description:An outbreak caused by 2019 novel coronavirus (2019-nCoV) was first identified in Wuhan City, Hubei Province, China. The new virus was later named SARS-CoV-2. The virus has affected tens of thousands of patients in the world. The infection of SARS-CoV-2 causes severe pneumonia and even death. It is urgently needed to find a therapeutic method to treat patients with SARS-CoV-2 infection. Studies showed that the surface spike (S) protein is essential for the coronavirus binding and entry of host cells. The heptad repeats 1 and 2 (HR1 and HR2) in the S protein play a decisive role in the fusion of the viral membrane with the host cell membrane. We predicted the HR1 and HR2 regions in S protein by sequence alignment. We simulated a computational model of HR1/2 regions and the fusion core. The binding energy of HR1 and HR2 of the fusion core was -33.4 kcal/mol. We then designed antivirus peptides by molecular dynamics simulation of the fusion core. The binding energy of HR2-based antiviral peptide to HR1 was -43.0 kcal/mol, which was stronger than the natural stage of the fusion core, suggesting that the predicted antiviral peptide can competitively bind with HR1 to prevent forming of the fusion core. The antiviral peptides can prevent SARS-CoV-2 membrane fusion and can potentially be used for the prevention and treatment of infections.

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Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor

Project description: Not available

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Drug repurposing for identification of potential inhibitors against SARS-CoV-2 spike receptor-binding domain: An <i>in silico</i> approach.

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Methylxanthines as Potential Inhibitor of SARS-CoV-2: an In Silico Approach.

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SARS-CoV-2 S Omicron Spike B.1.1.529

Project description: Not available

| EMPIAR-10947 | biostudies-other

In-silico design of a potential inhibitor of SARS-CoV-2 S protein.

Project description:The SARS-CoV-2 virus has caused a pandemic and is public health emergency of international concern. As of now, no registered therapies are available for treatment of coronavirus infection. The viral infection depends on the attachment of spike (S) glycoprotein to human cell receptor angiotensin-converting enzyme 2 (ACE2). We have designed a protein inhibitor (ΔABP-D25Y) targeting S protein using computational approach. The inhibitor consists of two α helical peptides homologues to protease domain (PD) of ACE2. Docking studies and molecular dynamic simulation revealed that the inhibitor binds exclusively at the ACE2 binding site of S protein. The computed binding affinity of the inhibitor is higher than the ACE2 and thus will likely out compete ACE2 for binding to S protein. Hence, the proposed inhibitor ΔABP-D25Y could be a potential blocker of S protein and receptor binding domain (RBD) attachment.

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<i>In silico</i> design of quadruplex aptamers against the spike protein of SARS-CoV-2.

Project description:Nucleic acid aptamers are short sequences of nucleic acid ligands that bind to a specific target molecule. Aptamers are experimentally nominated using the well-designed SELEX (systematic evolution of ligands by exponential enrichment) method. Here, we designed a new method for diagnosis and blocking SARS-CoV-2 based on G-quadruplex aptamer. This aptamer was developed against the receptor-binding domain (RBD) region of the spike protein. In the current study, ten quadruplex DNA aptamers entitled AP1, AP2, AP3, AP4, AP5, AP6, AP7, AP8, AP9, and AP10 were designed in silico and had high HADDOCK scores. One quadruplex aptamer sequence (AP1) was selected based on the interaction with RBD of SARS-CoV-2. Results showed that AP1 aptamer could be used as an agent in the diagnosis and therapy of SARS-CoV-2, although more works are still needed.

| S-EPMC8514331 | biostudies-literature

Perturbation of ACE2 Structural Ensembles by SARS-CoV-2 Spike Protein Binding.

Project description:The human ACE2 enzyme serves as a critical first recognition point of coronaviruses, including SARS-CoV-2. In particular, the extracellular domain of ACE2 interacts directly with the S1 tailspike protein of the SARS-CoV-2 virion through a broad protein-protein interface. Although this interaction has been characterized by X-ray crystallography, these structures do not reveal significant differences in the ACE2 structure upon S1 protein binding. In this work, using several all-atom molecular dynamics simulations, we show persistent differences in the ACE2 structure upon binding. These differences are determined with the linear discriminant analysis (LDA) machine learning method and validated using independent training and testing datasets, including long trajectories generated by D. E. Shaw Research on the Anton 2 supercomputer. In addition, long trajectories for 78 potent ACE2-binding compounds, also generated by D. E. Shaw Research, were projected onto the LDA classification vector in order to determine whether the ligand-bound ACE2 structures were compatible with S1 protein binding. This allows us to predict which compounds are "apo-like" versus "complex-like" and to pinpoint long-range ligand-induced allosteric changes in the ACE2 structure.

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