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1.
Computers in Biology and Medicine ; : 105574, 2022.
Article in English | ScienceDirect | ID: covidwho-1814282

ABSTRACT

With the emergence of Delta and Omicron variants, many other important variants of SARS-CoV-2, which cause Coronavirus disease-2019, including A.30, are reported to increase the concern created by the global pandemic. The A.30 variant, reported in Tanzania and other countries, harbors spike gene mutations that help this strain to bind more robustly and to escape neutralizing antibodies. The present study uses molecular modelling and simulation-based approaches to investigate the key features of this strain that result in greater infectivity. The protein-protein docking results for the spike protein demonstrated that additional interactions, particularly two salt-bridges formed by the mutated residue Lys484, increase binding affinity, while the loss of key residues at the N terminal domain (NTD) result in a change to binding conformation with monoclonal antibodies, thus escaping their neutralizing effects. Moreover, we deeply studied the atomic features of these binding complexes through molecular simulation, which revealed differential dynamics when compared to wild type. Analysis of the binding free energy using MM/GBSA revealed that the total binding free energy (TBE) for the wild type receptor-binding domain (RBD) complex was −58.25 kcal/mol in contrast to the A.30 RBD complex, which reported −65.59 kcal/mol. The higher TBE for the A.30 RBD complex signifies a more robust interaction between A.30 variant RBD with ACE2 than the wild type, allowing the variant to bind and spread more promptly. The BFE for the wild type NTD complex was calculated to be −65.76 kcal/mol, while the A.30 NTD complex was estimated to be −49.35 kcal/mol. This shows the impact of the reported substitutions and deletions in the NTD of A.30 variant, which consequently reduce the binding of mAb, allowing it to evade the immune response of the host. The reported results will aid the development of cross-protective drugs against SARS-CoV-2 and its variants.

2.
RSC advances ; 11(48):30132-30147, 2021.
Article in English | EuropePMC | ID: covidwho-1812811

ABSTRACT

Continuing reports of new SARS-CoV-2 variants have caused worldwide concern and created a challenging situation for clinicians. The recently reported variant B.1.618, which possesses the E484K mutation specific to the receptor-binding domain (RBD), as well as two deletions of Tyr145 and His146 at the N-terminal binding domain (NTD) of the spike protein, must be studied in depth to devise new therapeutic options. Structural variants reported in the RBD and NTD may play essential roles in the increased pathogenicity of this SARS-CoV-2 new variant. We explored the binding differences and structural-dynamic features of the B.1.618 variant using structural and biomolecular simulation approaches. Our results revealed that the E484K mutation in the RBD slightly altered the binding affinity through affecting the hydrogen bonding network. We also observed that the flexibility of three important loops in the RBD required for binding was increased, which may improve the conformational optimization and consequently binding of the new variant. Furthermore, we found that deletions of Tyr145 and His146 at the NTD reduced the binding affinity of the monoclonal antibody (mAb) 4A8, and that the hydrogen bonding network was significantly affected consequently. This data show that the new B.1.618 variant is an antibody-escaping variant with slightly altered ACE2–RBD affinity. Moreover, we provide insights into the binding and structural-dynamics changes resulting from novel mutations in the RBD and NTD. Our results suggest the need for further in vitro and in vivo studies that will facilitate the development of possible therapies for new variants such as B.1.618. This study explored the binding patterns of the wild type and B.1.618 variant using which revealed that the B.1.618 variant possess a stronger binding affinity for the host ACE2 and escape the neutralizing antibodies.

3.
RSC advances ; 12(12):7318-7327, 2022.
Article in English | EuropePMC | ID: covidwho-1787253

ABSTRACT

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world. The omicron variant is reported to be highly contagious with antibody-escaping activity. The emergence of antibody-escaping variants is alarming, and thus the quick discovery of small molecule inhibitors is needed. Hence, the current study uses computational drug screening and molecular dynamics simulation approaches (replicated) to identify novel drugs that can inhibit the binding of the receptor-binding domain (RBD) with hACE2. Screening of the North African, East African and North-East African medicinal compound databases by employing a multi-step screening approach revealed four compounds, namely (−)-pipoxide (C1), 2-(p-hydroxybenzyl) benzofuran-6-ol (C2), 1-(4-hydroxy-3-methoxyphenyl)-2-{4-[(E)-3-hydroxy-1-propenyl]-2-methoxyphenoxy}-1,3-propanediol (C3), and Rhein (C4), with excellent anti-viral properties against the RBD of the omicron variant. Investigation of the dynamics demonstrates stable behavior, good residue flexibility profiles, and structural compactness. Validation of the top hits using computational bioactivity analysis, binding free energy calculations and dissociation constant (KD) analysis also indicated the anti-viral properties of these compounds. In conclusion, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging omicron variant of SARS-CoV-2. A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world.

4.
Molecules ; 27(7)2022 Apr 06.
Article in English | MEDLINE | ID: covidwho-1776294

ABSTRACT

The continued emergence of human coronaviruses (hCoVs) in the last few decades has posed an alarming situation and requires advanced cross-protective strategies against these pandemic viruses. Among these, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), and Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) have been highly associated with lethality in humans. Despite the challenges posed by these viruses, it is imperative to develop effective antiviral therapeutics and vaccines for these human-infecting viruses. The proteomic similarity between the receptor-binding domains (RBDs) among the three viral species offers a potential target for advanced cross-protective vaccine designs. In this study, putative immunogenic epitopes including Cytotoxic T Lymphocytes (CTLs), Helper T Lymphocytes (HTLs), and Beta-cells (B-cells) were predicted for each RBD-containing region of the three highly pathogenic hCoVs. This was followed by the structural organization of peptide- and mRNA-based prophylactic vaccine designs. The validated 3D structures of these epitope-based vaccine designs were subjected to molecular docking with human TLR4. Furthermore, the CTL and HTL epitopes were processed for binding with respective human Lymphocytes Antigens (HLAs). In silico cloning designs were obtained for the prophylactic vaccine designs and may be useful in further experimental designs. Additionally, the epitope-based vaccine designs were evaluated for immunogenic activity through immune simulation. Further studies may clarify the safety and efficacy of these prophylactic vaccine designs through experimental testing against these human-pathogenic coronaviruses.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevention & control , Epitopes, B-Lymphocyte , Epitopes, T-Lymphocyte , Humans , Molecular Docking Simulation , Proteomics , RNA, Messenger , Vaccines, Subunit/chemistry , Vaccinology
5.
Nat Commun ; 13(1): 1788, 2022 Apr 04.
Article in English | MEDLINE | ID: covidwho-1773979

ABSTRACT

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the generation of variants that may diminish host immune responses to vaccine formulations. Here we show a registered observational clinical trial (NCT04795414), we assess the safety and immunogenicity of the inactivated SARS-CoV-2 vaccine BBIBP-CorV in a cohort of 1006 vaccine recipients. No serious adverse events are observed during the term of the study. Detectable virus-specific antibody is measured and determined to be neutralizing in 698/760 (91.84%) vaccine recipients on day 28 post second vaccine dose and in 220/581 (37.87%) vaccine recipients on day 180 post second vaccine dose, whereas vaccine-elicited sera show varying degrees of reduction in neutralization against a range of key SARS-CoV-2 variants, including variant Alpha, Beta, Gamma, Iota, and Delta. Our work show diminished neutralization potency against multiple variants in vaccine-elicited sera, which indicates the potential need for additional boost vaccinations.


Subject(s)
COVID-19 Vaccines , COVID-19 , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , SARS-CoV-2/genetics
6.
Comput Biol Med ; 145: 105462, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1768008

ABSTRACT

The emergence of variants and the reports of co-infection caused by Candida auris in COVID-19 patients adds a further complication to the global pandemic situation. To date, no effective therapy is available for C. auris infections. Thus, characterization of therapeutic targets and designing effective vaccine candidates using subtractive proteomics and immune-informatics approaches is useful tool in controlling the emerging infections associated with SARS-CoV-2. In the current study, subtractive proteomics-assisted annotation of the vaccine targets was performed, which revealed seven vaccine targets. An immunoinformatic-driven approach was then employed to map protein-specific and proteome-wide immunogenic peptides (CTL, B cell, and HTL) for the design of multi-epitope vaccine candidates (MEVCs). The results demonstrated that the vaccine candidates possess strong antigenic features (>0.4 threshold score) and are classified as non-allergenic. Validation of the designed MEVCs through molecular docking, in-silico cloning, and immune simulation further demonstrated the efficacy of the vaccines by producing immune factor titers (ranging from 2500 to 16000 au/mL) i.e., IgM, IgG, IL-6, and Interferon-α. In conclusion, the current study provides a strong impetus in designing anti-fungal strategies against Candida auris.

7.
Global Mental Health ; : No Pagination Specified, 2022.
Article in English | APA PsycInfo | ID: covidwho-1758035

ABSTRACT

Background Risk perception among nurses after the COVID-19 pandemic is a crucial factor affecting their attitudes and willingness to work in clinics. Those with poor psychological status could perceive risks sensitively as fears or threats that are discouraging. This article aimed to determine whether psychological outcomes, including post-traumatic stress disorder (PTSD), depression, anxiety, and insomnia, following the COVID-19 pandemic were differentially related to the risk perceptions of nurses working in clinics and increased perceived risk. Method The participants were 668 nurse clinicians from five local hospitals. Risk perceptions and psychological outcomes were measured by adapted questionnaires via the Internet. Latent profile analysis (LPA) identified subgroups of individuals who showed similar profiles regarding the perceived risks in nursing. Multinomial regression and probit regression were used to examine the extent to which sociodemographic and psychological outcomes predicted class membership. Results LPA revealed four classes: groups with low-, mild-, moderate-, and high-level risk perceptions. Membership of the high-level risk perception class was predicted by the severity of psychological outcomes. Anxiety significantly accounted for a moderate increase in risk perceptions, while the symptoms of insomnia, depression, and PTSD accelerated the increase to the high level of risk perception class. Conclusions By classifying groups of nurse clinicians sharing similar profiles regarding risk perceptions and then exploring associated predictors, this study shows the psychological outcomes after COVID-19 significantly impacted pandemic-associated risk perceptions and suggests intervening in nurses' psychological outcomes while simultaneously focusing on work-related worries is important following the outbreak of COVID-19. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

8.
RSC Adv ; 12(12): 7318-7327, 2022 Mar 01.
Article in English | MEDLINE | ID: covidwho-1747166

ABSTRACT

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world. The omicron variant is reported to be highly contagious with antibody-escaping activity. The emergence of antibody-escaping variants is alarming, and thus the quick discovery of small molecule inhibitors is needed. Hence, the current study uses computational drug screening and molecular dynamics simulation approaches (replicated) to identify novel drugs that can inhibit the binding of the receptor-binding domain (RBD) with hACE2. Screening of the North African, East African and North-East African medicinal compound databases by employing a multi-step screening approach revealed four compounds, namely (-)-pipoxide (C1), 2-(p-hydroxybenzyl) benzofuran-6-ol (C2), 1-(4-hydroxy-3-methoxyphenyl)-2-{4-[(E)-3-hydroxy-1-propenyl]-2-methoxyphenoxy}-1,3-propanediol (C3), and Rhein (C4), with excellent anti-viral properties against the RBD of the omicron variant. Investigation of the dynamics demonstrates stable behavior, good residue flexibility profiles, and structural compactness. Validation of the top hits using computational bioactivity analysis, binding free energy calculations and dissociation constant (K D) analysis also indicated the anti-viral properties of these compounds. In conclusion, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging omicron variant of SARS-CoV-2.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-316840

ABSTRACT

The global pandemic caused by a single-stranded RNA (ssRNA) virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still at its peak, with new cases being reported daily. Though the vaccinations are done on a massive scale, the frequent mutations in the viral gene and resilience of the future strains could be more problematic. Therefore, there is always a need for new compounds to be available for therapeutic studies. We carried out the present research to discover potential drug compounds against the SARS-CoV-2 main protease. A total of 16,000 drug-like small molecules from the ChemBridge database were virtually screened to obtain the top hits. As a result, 1032 hits were selected based on their docking scores. Next, these structures were prepared for molecular docking, and each small molecule was docked into the active site of the Mpro. Only those compounds with strong interactions with the active site residues and had the highest docking score were subjected to molecular dynamics (MD) simulation. The post-simulation analyses were carried out using the in-built GROMACS commands to gauge the stability, flexibility, and compactness. Principal component analysis (PCA) and hydrogen bonding were also calculated to observe trends and affinity of the drugs towards the target. Among the five top compounds, C1, C3, and C4 revealed strong interaction with the target’s active site and remained highly stable throughout the simulation. We believe the predicted compounds in this study could be potential inhibitors in the natural system and must be considered for further practice.

10.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-314041

ABSTRACT

Background: The prolific spread of COVID-19 caused by a novel coronavirus (SARS-CoV-2) from its epicenter in Wuhan, China, to every nook and cranny of the world after December 2019, jeopardize the prevailing health system in the world and has raised serious concerns about human safety. To date efforts are continuing to design small molecule inhibitor, vaccines and many other therapeutic options are practiced but their final therapeutic potential is still to be tested. Using the old drug or vaccine or peptides could aid this process to avoid such long experimental procedure. Results: : Hence, here we have repurposed a small peptide (ATLQAIAS) from the previous study which reported the inhibitory effects of this peptide. We used in silico mutagenesis approach to design more peptides from the native wild peptide, which revealed that substitutions (T2W, T2Y, L3R and A5W) could increase the binding affinity of the peptide towards the 3CLpro. Furthermore, using MD simulation and free energy calculation confirmed its dynamics stability and stronger binding affinities. Per-residues energy decomposition analysis revealed that the specified substitution significantly increased the binding affinity at residue level. Conclusion: Our wide-ranging analyses of binding affinities disclosed that our designed peptide owns the potential to hinder the SARS-CoV-2 and will reduce the progression of SARs-CoV-2-borne pneumonia. Our analysis strongly suggests the experimental and clinical validation of these peptides to curtail the recent corona outbreak.

11.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-314037

ABSTRACT

Most recently, an outbreak of severe pneumonia caused by the infection of 2019-nCoV, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Therefore, the role and inhibition of nsp12 are indispensable. Since there is no crystallographic structure of RdRp is available, so, here, we present the 3-dimensional structure of the 2019-nCoV nsp12 polymerase using a computational approach. nsp12 of 2019-nCoV possesses an architecture common to all viral polymerases as well as a large N-terminal extension. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity, and acts as a template for the design of novel antiviral therapeutics. Besides, the experimental structure could reveal the organization in a more sophisticated way. Furthermore, the ancestral state reconstruction suggests the possible evolution of nCoV in Wuhan China and its dispersal to the USA. The result of our analyses postulates the possible dispersal of nCoV from the USA and Shenzhen back to Wuhan. This disclosing of valuable knowledge regarding the 3D structure of 2019-nCoV nsp12 architecture, ancestral relation, and dispersion pattern could help to design effective therapeutic candidates against the coronaviruses and design robust preventive measurements.

12.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-308156

ABSTRACT

Background: With the outbreak of novel coronavirus, the global epidemic prevention form is severe. Purpose: This paper aimed to investigate the association between meteorological factors (temperature, precipitation and relative humidity) and the daily new cases in Wuhan. Methods: generalized linear model was built to evaluate the link between daily average temperature and the new cases COVID-19. Spearman rank correlation coefficient was used to investigate the association between temperature, relative humidity, precipitation and the daily new cases COVID-19. Result: The correlation coefficient for daily average temperature, relative humidity, precipitation and NCP were 0.11, -0.083 and 0.17, respectively. The maximal effect of temperature on the new cases NCP appeared on Lag0. Conclusion: The variation of temperature had an effect on the daily new cases.

13.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-325163

ABSTRACT

We assessed the safety and immunogenicity of an inactivated SARS-CoV-2 vaccine BBIBP-CorV, especially measured the resistance of four global variants of concern: Lineage B.1.1.7, Lineage B.1.351, Lineage P.1, and Lineage B.1.526 to neutralizing activity of vaccine-elicited sera. Among 1006 enrolled participants, no serious adverse event was reported within 28 days post-vaccination. Seroconversion of neutralizing antibodies was seen in 698 (91.84%) of 760 healthcare workers, and the geometric mean titres (GMTs) of neutralizing antibody titre was 62.68 (57.02–68.91) after the second immunization. We found that 57 (12.13%), 99 (20.97%), and 114 (24.26%) vaccine-elicited sera showed complete or partial loss of neutralizing activity against lineage B.1.1.7, lineage B.1.526, and lineage P.1, respectively, while 199 (42.34%) vaccine-elicited sera preserved neutralizing activity against lineage B.1.351, albeit at relatively low dilutions. These data indicated that humoral responses against SARS-CoV-2 could be effectively induced in vaccine recipients, although diminished neutralization potency against multiple variants was observed.

14.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325082

ABSTRACT

Background: Corona Virus Disease 2019 (CVID-19) is spreading across the world and the epidemic is also a great stress event for individuals which may trigger lots of mental health issue . This study aims to investigate the relationship between depressive symptoms and stress in individuals with infectious history of COVID-19 in Wuhan and the mediating effect of purpose in life. Method: A total of 128 individuals with infectious history of COVID-19 who were discharged from designated hospital and furtherly accepted health management of 14-day rehabilitation, isolation and medical observation at Qingshan District Rehabilitation Station in Wuhan were selected for the testing of Center for Epidemiologic Studies Depression Scale (CES-D), Impact of Event Scale (IES) and purpose-in-life test (PLT). Results: : The depressive emotion, somatic symptoms and total score of CES-D in male group were significantly lower than that of in female participants ( P < 0.001 ). The total score of CES-D was negatively correlated with all factors of PLT and positively correlated with all factors in IES ( P<0.05 or 0.01 ). The feeling of life, life goal, intrusiveness and awareness had significant predictive effects on the total score of CES-D( P<0.05 or 0.01 ), which could explain 69.3% of variations in the total score of CES-D. The purpose in life played a partial mediating effect between the stress and depressive symptoms in individuals with infectious history of COVID-19, and the mediating effect accounted for 13.33% of the total effect. Conclusions: : The females with infectious history of COVID-19 had more severe symptoms of depression. The stress of COVID-19 infectious history had predictive effect on depressive symptoms and purpose in life was mediator between stress and depressive symptoms.

15.
Mol Divers ; 2022 Feb 09.
Article in English | MEDLINE | ID: covidwho-1681347

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 continues to mutate. Numerous studies have indicated that this viral mutation, particularly in the receptor-binding domain area, may increase the viral affinity for human angiotensin-converting enzyme 2 (hACE2), the receptor for viral entry into host cells, thereby increasing viral virulence and transmission. In this study, we investigated the binding affinity of SARS-CoV-2 variants (Delta plus, Iota, Kappa, Mu, Lambda, and C.1.2) on hACE2 using computational modeling with a protein-protein docking approach. The simulation results indicated that there were differences in the interactions between the RBD and hACE2, including hydrogen bonding, salt bridge interactions, non-bonded interactions, and binding free energy differences among these variants. Molecular dynamics simulations revealed that mutations in the RBD increase the stability of the hACE2-spike protein complex relative to the wild type, following the global stability trend and increasing the binding affinity. The value of binding-free energy calculated using molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) indicated that all mutations in the spike protein increased the contagiousness of SARS-CoV-2 variants. The findings of this study provide a foundation for developing effective interventions against these variants. Computational modeling elucidates that the spike protein of SARS-CoV-2 variants binds considerably stronger than the wild-type to hACE2.

16.
Comput Biol Med ; 143: 105235, 2022 Jan 26.
Article in English | MEDLINE | ID: covidwho-1649005

ABSTRACT

The global pandemic caused by a single-stranded RNA (ssRNA) virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still at its peak, with new cases being reported daily. Although the vaccines have been administered on a massive scale, the frequent mutations in the viral gene and resilience of the future strains could be more problematic. Therefore, new compounds are always needed to be available for therapeutic approaches. We carried out the present study to discover potential drug compounds against the SARS-CoV-2 main protease (Mpro). A total of 16,000 drug-like small molecules from the ChemBridge database were virtually screened to obtain the top hits. As a result, 1032 hits were selected based on their docking scores. Next, these structures were prepared for molecular docking, and each small molecule was docked into the active site of the Mpro. Only compounds with solid interactions with the active site residues and the highest docking score were subjected to molecular dynamics (MD) simulation. The post-simulation analyses were carried out using the in-built GROMACS tools to gauge the stability, flexibility, and compactness. Principal component analysis (PCA) and hydrogen bonding were also calculated to observe trends and affinity of the drugs towards the target. Among the five top compounds, C1, C3, and C6 revealed strong interaction with the target's active site and remained highly stable throughout the simulation. We believe the predicted compounds in this study could be potential inhibitors in the natural system and can be utilized in designing therapeutic strategies against the SARS-CoV-2.

17.
IEEE J Biomed Health Inform ; 26(1): 172-182, 2022 01.
Article in English | MEDLINE | ID: covidwho-1642566

ABSTRACT

Till March 31st, 2021, the coronavirus disease 2019 (COVID-19) had reportedly infected more than 127 million people and caused over 2.5 million deaths worldwide. Timely diagnosis of COVID-19 is crucial for management of individual patients as well as containment of the highly contagious disease. Having realized the clinical value of non-contrast chest computed tomography (CT) for diagnosis of COVID-19, deep learning (DL) based automated methods have been proposed to aid the radiologists in reading the huge quantities of CT exams as a result of the pandemic. In this work, we address an overlooked problem for training deep convolutional neural networks for COVID-19 classification using real-world multi-source data, namely, the data source bias problem. The data source bias problem refers to the situation in which certain sources of data comprise only a single class of data, and training with such source-biased data may make the DL models learn to distinguish data sources instead of COVID-19. To overcome this problem, we propose MIx-aNd-Interpolate (MINI), a conceptually simple, easy-to-implement, efficient yet effective training strategy. The proposed MINI approach generates volumes of the absent class by combining the samples collected from different hospitals, which enlarges the sample space of the original source-biased dataset. Experimental results on a large collection of real patient data (1,221 COVID-19 and 1,520 negative CT images, and the latter consisting of 786 community acquired pneumonia and 734 non-pneumonia) from eight hospitals and health institutions show that: 1) MINI can improve COVID-19 classification performance upon the baseline (which does not deal with the source bias), and 2) MINI is superior to competing methods in terms of the extent of improvement.


Subject(s)
COVID-19 , Deep Learning , Algorithms , Humans , Pandemics , SARS-CoV-2
18.
Int J Biol Macromol ; 200: 438-448, 2022 Mar 01.
Article in English | MEDLINE | ID: covidwho-1633972

ABSTRACT

As SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) continues to inflict chaos globally, a new variant officially known as B.1.1.529 was reported in South Africa and was found to harbor 30 mutations in the spike protein. It is too early to speculate on transmission and hospitalizations. Hence, more analyses are required, particularly to connect the genomic patterns to the phenotypic attributes to reveal the binding differences and antibody response for this variant, which can then be used for therapeutic interventions. Given the urgency of the required analysis and data on the B.1.1.529 variant, we have performed a detailed investigation to provide an understanding of the impact of these novel mutations on the structure, function, and binding of RBD to hACE2 and mAb to the NTD of the spike protein. The differences in the binding pattern between the wild type and B.1.1.529 variant complexes revealed that the key substitutions Asn417, Ser446, Arg493, and Arg498 in the B.1.1.529 RBD caused additional interactions with hACE2 and the loss of key residues in the B.1.1.529 NTD resulted in decreased interactions with three CDR regions (1-3) in the mAb. Further investigation revealed that B.1.1.529 displayed a stable dynamic that follows a global stability trend. In addition, the dissociation constant (KD), hydrogen bonding analysis, and binding free energy calculations further validated the findings. Hydrogen bonding analysis demonstrated that significant hydrogen bonding reprogramming took place, which revealed key differences in the binding. The total binding free energy using MM/GBSA and MM/PBSA further validated the docking results and demonstrated significant variations in the binding. This study is the first to provide a basis for the higher infectivity of the new SARS-CoV-2 variants and provides a strong impetus for the development of novel drugs against them.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antibodies/chemistry , Antibodies/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/metabolism , Humans , Hydrogen Bonding , Immune Evasion , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding/immunology , Protein Domains/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
20.
Comb Chem High Throughput Screen ; 2022 Jan 11.
Article in English | MEDLINE | ID: covidwho-1622462
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