Analysis of Intermediate Hosts and Susceptible Animals of SARS-CoV-2 by Computational Methods

COVID-19, caused by SARS-CoV-2 with major symptom of pneumonia is bringing huge disasters to the people around the world. Recent research indicates that the natural host of SARS-CoV-2 may be bats, but its intermediate host is still unclear. Only by finding natural and intermediate host for SARS-CoV-2 can cut off the source and prevent the virus from being transmitted to humans. In this study, we established a new method for the mining of intermediate host. We selected 82 representative ACE2 sequences from the 1000 sequences with the closest homology to the human ACE2 protein. All these selected ACE2 proteins were modeled by homology modeling. The potential natural and intermediate hosts, as well as susceptible animals of SARS-CoV-2 were analyzed systematically by calculating the binding free energy of ACE2 protein with the RBD of SARS-CoV-2. Based on this study, Rhinolophus sinicus was suggested to be the natural host, and the virus may be transmitted directly from bats to humans. Primates, some wild Felidae, civet, goats, spotted hyenas and golden hamsters may be susceptible to SARS-CoV-2 and could be intermediate hosts, while pangolins are unlikely to be intermediate hosts, and birds and reptiles are not intermediate hosts. Mice, rats and guinea pig are not susceptible to SARS-CoV-2. Considering the possible susceptibility of non-human primates, goats and golden hamsters, they can be used as experimental animals directly for the SARS-CoV-2 infection models without transgenic operation. Herein, the possible candidates of natural and intermediate hosts of SARS-CoV-2 were suggested, which will provide guiding significance for subsequent researches.<br>

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In Silico Analysis of Intermediate Hosts and Susceptible Animals of SARS-CoV-2

10.26434/chemrxiv.12057996.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Canrong Wu ◽

Mengzhu Zheng ◽

Yueying Yang ◽

Mingxue Li ◽

Yang Liu ◽

...

Keyword(s):

Intermediate Host ◽

Binding Free Energy ◽

In Silico Analysis ◽

Natural Host ◽

Intermediate Hosts ◽

Golden Hamsters ◽

The People ◽

Infection Models ◽

Spotted Hyenas ◽

Silico Analysis

COVID-19, caused by SARS-CoV-2 with major symptom of pneumonia is bringing huge disasters to the people around the world. Recent research indicates that the natural host of SARS-CoV-2 may be bats, but its intermediate host is still unclear. Only by finding natural and intermediate host for SARS-CoV-2 can cut off the source and prevent the virus from being transmitted to humans. In this study, we established a new method for the mining of intermediate host. We selected 82 representative ACE2 sequences from the 1000 sequences with the closest homology to the human ACE2 protein. All these selected ACE2 proteins were modeled by homology modeling. The potential natural and intermediate hosts, as well as susceptible animals of SARS-CoV-2 were analyzed systematically by calculating the binding free energy of ACE2 protein with the RBD of SARS-CoV-2. Based on this study, Rhinolophus sinicus was suggested to be the natural host, and the virus may be transmitted directly from bats to humans. Primates, some wild Felidae, civet, goats, spotted hyenas and golden hamsters may be susceptible to SARS-CoV-2 and could be intermediate hosts, while pangolins are unlikely to be intermediate hosts, and birds and reptiles are not intermediate hosts. Mice, rats and guinea pig are not susceptible to SARS-CoV-2. Considering the possible susceptibility of non-human primates, goats and golden hamsters, they can be used as experimental animals directly for the SARS-CoV-2 infection models without transgenic operation. Herein, the possible candidates of natural and intermediate hosts of SARS-CoV-2 were suggested, which will provide guiding significance for subsequent researches.<br>

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Current Status of Putative Animal Sources of SARS-CoV-2 Infection in Humans: Wildlife, Domestic Animals and Pets

Microorganisms ◽

10.3390/microorganisms9040868 ◽

2021 ◽

Vol 9 (4) ◽

pp. 868

Author(s):

Max Maurin ◽

Florence Fenollar ◽

Oleg Mediannikov ◽

Bernard Davoust ◽

Christian Devaux ◽

...

Keyword(s):

Animal Species ◽

Biological Properties ◽

Experimental Models ◽

Current Data ◽

The Body ◽

Receptor Expression ◽

Current Status ◽

Susceptible Animal

SARS-CoV-2 is currently considered to have emerged from a bat coronavirus reservoir. However, the real natural cycle of this virus remains to be elucidated. Moreover, the COVID-19 pandemic has led to novel opportunities for SARS-CoV-2 transmission between humans and susceptible animal species. In silico and in vitro evaluation of the interactions between the SARS-CoV-2 spike protein and eucaryotic angiotensin-converting enzyme 2 (ACE2) receptor have tentatively predicted susceptibility to SARS-CoV-2 infection of several animal species. Although useful, these data do not always correlate with in vivo data obtained in experimental models or during natural infections. Other host biological properties may intervene such as the body temperature, level of receptor expression, co-receptor, restriction factors, and genetic background. The spread of SARS-CoV-2 also depends on the extent and duration of viral shedding in the infected host as well as population density and behaviour (group living and grooming). Overall, current data indicate that the most at-risk interactions between humans and animals for COVID-19 infection are those involving certain mustelids (such as minks and ferrets), rodents (such as hamsters), lagomorphs (especially rabbits), and felines (including cats). Therefore, special attention should be paid to the risk of SARS-CoV-2 infection associated with pets.

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Susceptibility of animal species to experimental SARS-CoV-2 (Coronaviridae: Coronavirinae: Betacoronavirus; Sarbecovirus) infection

Voprosy Virusologii ◽

10.36233/0507-4088-47 ◽

2021 ◽

Vol 66 (2) ◽

pp. 103-111

Author(s):

N. V. Petrova ◽

K. K. Ganina ◽

S. A. Tarasov

Keyword(s):

Neutralizing Antibodies ◽

Scientific Community ◽

Animal Species ◽

Vaccine Development ◽

Clinical Symptoms ◽

Experimental Models ◽

Laboratory Animals ◽

Susceptible Animal ◽

Advantages And Disadvantages ◽

Coronavirus Infection

Due to the new coronavirus infection pandemic, the global scientific community has been forced to change the direction of the most research, focusing on vaccine development as well as the search for new antiviral drugs to treat COVID-19. The choice of experimental models, timeframe and approaches for evaluating drugs and vaccines under development is crucial for the development of effective measures to prevent and control this disease.The purpose of this review was to summarize the relevant data concerning the susceptibility of laboratory animals to SARS-CoV-2. This paper describes the most virus-susceptible animal species that can be used to reproduce coronavirus infection, stressing the main advantages and disadvantages of each of them.According to the latest data, small rodents (Rodentia) and non-human primates (Strepsirrhini) are commonly used in the scientific community to model coronavirus infection. The viral load in the upper and lower parts of the respiratory system, clinical symptoms of infection (weight loss, body temperature and general health status), pathomorphological picture in target organs and the production of antibodies after infection are considered to the main markers of pathology. Despite the vast amount of data, none of the described models of SARS-CoV-2 infection may be considered a gold standard, since they do not reproduce all spectrum of morphological and pathogenetic mechanisms of infection, and do not fully reflect the clinical picture observed in patients in human population.Based on the analyzed literature data, we suppose that Syrian hamster (Mesocricetus auratus) and mice (Muridae) expressing the angiotensin converting enzyme receptor 2 (ACE2) are the most suitable animal species for their use in experiments with SARS-CoV-2 infection. The development of neutralizing antibodies makes it possible to evaluate the efficacy of vaccines, while the course and severity of symptoms infection makes the use of mice and hamsters especially popular for screening pharmacological substances with antiviral mechanism of action, when their administration can prevent or slow the disease progression.

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Ultrastructure and Drug Metabolism in the Developing Guinea Pig

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100073131 ◽

1973 ◽

Vol 31 ◽

pp. 538-539

Author(s):

W. Kuenzig ◽

M. Boublik ◽

J.J. Kamm ◽

J.J. Burns

Keyword(s):

Guinea Pig ◽

Metabolic Activity ◽

Animal Species ◽

Adult Animal ◽

Smooth Endoplasmic Reticulum ◽

Fetal Life ◽

Mixed Function Oxidase ◽

Cytochrome P 450 ◽

Microsomal Mixed Function Oxidase ◽

Mixed Function Oxidase Activity

Unlike a variety of other animal species, such as the rabbit, mouse or rat, the guinea pig has a relatively long gestation period and is a more fully developed animal at birth. Kuenzig et al. reported that drug metabolic activity which increases very slowly during fetal life, increases rapidly after birth. Hepatocytes of a 3-day old neonate metabolize drugs and reduce cytochrome P-450 at a rate comparable to that observed in the adult animal. Moreover the administration of drugs like phenobarbital to pregnant guinea pigs increases the microsomal mixed function oxidase activity already in the fetus.Drug metabolic activity is, generally, localized within the smooth endoplasmic reticulum (SER) of the hepatocyte.

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Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648055 ◽

1976 ◽

Vol 36 (02) ◽

pp. 401-410 ◽

Cited By ~ 6

Author(s):

Buichi Fujttani ◽

Toshimichi Tsuboi ◽

Kazuko Takeno ◽

Kouichi Yoshida ◽

Masanao Shimizu

Keyword(s):

Guinea Pig ◽

Acetylsalicylic Acid ◽

Guinea Pigs ◽

Glass Bead ◽

Animal Species ◽

Inhibitory Effect ◽

Rabbit Platelet ◽

Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

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Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

10.26434/chemrxiv.11364884.v2 ◽

2020 ◽

Cited By ~ 3

Author(s):

Christina Schindler ◽

Hannah Baumann ◽

Andreas Blum ◽

Dietrich Böse ◽

Hans-Peter Buchstaller ◽

...

Keyword(s):

Free Energy ◽

Drug Discovery ◽

Large Scale ◽

Active Drug ◽

Binding Free Energy ◽

Free Energy Calculations ◽

Energy Calculation ◽

Large Scale Assessment ◽

New Public ◽

Binding Free Energy Calculations

Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>

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Automated, Accurate, and Scalable Relative Protein-Ligand Binding Free Energy Calculations using Lambda Dynamics

10.26434/chemrxiv.12781310.v1 ◽

2020 ◽

Author(s):

E. Prabhu Raman ◽

Thomas J. Paul ◽

Ryan L. Hayes ◽

Charles L. Brooks III

Keyword(s):

Free Energy ◽

Ligand Binding ◽

Binding Affinity ◽

Binding Free Energy ◽

Computational Cost ◽

Combinatorial Libraries ◽

Free Energy Calculations ◽

Lead Optimization ◽

Efficient Estimation ◽

Lead Compound

<p>Accurate predictions of changes to protein-ligand binding affinity in response to chemical modifications are of utility in small molecule lead optimization. Relative free energy perturbation (FEP) approaches are one of the most widely utilized for this goal, but involve significant computational cost, thus limiting their application to small sets of compounds. Lambda dynamics, also rigorously based on the principles of statistical mechanics, provides a more efficient alternative. In this paper, we describe the development of a workflow to setup, execute, and analyze Multi-Site Lambda Dynamics (MSLD) calculations run on GPUs with CHARMm implemented in BIOVIA Discovery Studio and Pipeline Pilot. The workflow establishes a framework for setting up simulation systems for exploratory screening of modifications to a lead compound, enabling the calculation of relative binding affinities of combinatorial libraries. To validate the workflow, a diverse dataset of congeneric ligands for seven proteins with experimental binding affinity data is examined. A protocol to automatically tailor fit biasing potentials iteratively to flatten the free energy landscape of any MSLD system is developed that enhances sampling and allows for efficient estimation of free energy differences. The protocol is first validated on a large number of ligand subsets that model diverse substituents, which shows accurate and reliable performance. The scalability of the workflow is also tested to screen more than a hundred ligands modeled in a single system, which also resulted in accurate predictions. With a cumulative sampling time of 150ns or less, the method results in average unsigned errors of under 1 kcal/mol in most cases for both small and large combinatorial libraries. For the multi-site systems examined, the method is estimated to be more than an order of magnitude more efficient than contemporary FEP applications. The results thus demonstrate the utility of the presented MSLD workflow to efficiently screen combinatorial libraries and explore chemical space around a lead compound, and thus are of utility in lead optimization.</p>

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Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

10.26434/chemrxiv.8398055 ◽

2019 ◽

Author(s):

David Wright ◽

Fouad Husseini ◽

Shunzhou Wan ◽

Christophe Meyer ◽

Herman Van Vlijmen ◽

...

Keyword(s):

Free Energy ◽

Surface Area ◽

Binding Free Energy ◽

Normal Mode Analysis ◽

Binding Mode ◽

Accessible Surface Area ◽

Solvent Accessible Surface Area ◽

Mode Analysis ◽

Energy Calculation ◽

Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

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Association/dissociation Mechanisms of Intrinsically Disordered Region of Protein Beyond Conformational Selection and Induced Fit

10.26434/chemrxiv.9874379 ◽

2019 ◽

Author(s):

Duy Phuoc Tran ◽

Akio Kitao

Keyword(s):

Free Energy ◽

Transcriptional Activation ◽

Binding Free Energy ◽

Energy Structure ◽

Induced Fit ◽

Hydrogen Bond Formation ◽

Conformational Selection ◽

Intrinsically Disordered ◽

Intrinsically Disordered Region ◽

Dissociation Mechanisms

<p>We investigate association and dissociation mechanisms of a typical intrinsically disordered region (IDR), transcriptional activation subdomain of tumor repressor protein p53 (TAD-p53) with murine double-minute clone 2 protein (MDM2). Using the combination of cycles of association and dissociation parallel cascade molecular dynamics, multiple standard MD, and Markov state model, we are successful in obtaining the lowest free energy structure of MDM2/TAD-p53 complex as the structure very close to that in crystal without prior knowledge. This method also reproduces the experimentally measured standard binding free energy, and association and dissociation rate constants solely with the accumulated MD simulation cost of 11.675 μs, in spite of the fact that actual dissociation occurs in the order of a second. Although there exist a few complex intermediates with similar free energies, TAD-p53 first binds MDM2 as the second lowest free energy intermediate dominantly (> 90% in flux), taking a form similar to one of the intermediate structures in its monomeric state. The mechanism of this step has a feature of conformational selection. In the second step, dehydration of the interface, formation of π-π stackings of the side-chains, and main-chain relaxation/hydrogen bond formation to complete α-helix take place, showing features of induced fit. In addition, dehydration (dewetting) is a key process for the final relaxation around the complex interface. These results demonstrate a more fine-grained view of the IDR association/dissociation beyond classical views of protein conformational change upon binding.</p>

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