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1.
Tropical Journal of Natural Product Research ; 6(8):1336-1342, 2022.
Article in English | EMBASE | ID: covidwho-2033553

ABSTRACT

The COVID-19 pandemic, caused by the SARS-CoV-2, has prompted international concern. This research aims to find bioactive phytocompounds from the traditional herb Icacina trichantha (Oliv) that could be used as a possible SARS-CoV-2 nonstructural protein inhibitor. GC-MS analysis identified fifteen (15) phytocompounds. In silico molecular docking, drug-likeness, toxicity and prediction of these compounds’ substance activity spectra (PASS) were evaluated. The phytocompounds all have good binding energies, according to molecular docking. The phytocompound, 9,12-octadecanoic acid gave the best binding affinity of-24.98 kcal/mole. All of the identified compounds conformed to Lipinski’s Rule of Five (RO5). This showed that the identified I. trichantha (Oliv) compounds would have lower attrition rates during clinical trials and thus have a better chance of being marketed. The current findings suggest that the discovered phytocompounds of I. trichantha (Oliv) could be developed as a novel COVID-19 medication.

2.
Tropical Journal of Natural Product Research ; 6(8):1262-1267, 2022.
Article in English | EMBASE | ID: covidwho-2033552

ABSTRACT

The spike glycoprotein of SARS-Cov-2 is a therapeutic target for Covid-19 and mutations in the Receptor Binding Motif (RBM) may alter the binding properties of ligands proposed to inhibit viral entry. This study aimed to identify the existence of a mutation pattern in the RBMs of SARS-Cov-2 variants and study the effect on ligand binding interactions. RBM sequences were obtained using NCBI BLASTP and subjected to multiple and pairwise sequence alignment analysis. Hypothetical generations were drawn from the phylogenetic tree. The effect of mutation on ligand binding was studied by docking zafirlukast on selected RBMs. Molecular dynamics simulations were conducted to explain molecular interactions. The sequences at the same phylogenetic level showed higher similarity with the observed differences defined by the crystallized chain length. 6XDG_E, a leaf node sequence was 76% similar to 7NXA_E, a branch from the root, and had the highest mutation. Differences in sequence similarity across successive generations were based on mutations and crystallized chain length and the amino acid substitution is not predictable. Different bond types and binding affinities were observed as well as varying Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and Region of Gyration (RoG) values for the RBMs in different variants. The RMSD, RMSF, and RoG did not differ significantly in the bound and free states of RBM from specific variants suggesting that the observed differences are attributable to amino acid substitutions. This information is crucial for drug development intended to block SARS-Cov-2 entry.

3.
Acta Crystallographica: Section D, Structural Biology ; 78(9):1156-1170, 2022.
Article in English | Academic Search Complete | ID: covidwho-2018424

ABSTRACT

A remarkable number of SARS‐CoV‐2 variants and other as yet unmonitored lineages harbor amino‐acid substitutions with the potential to modulate the interface between the spike receptor‐binding domain (RBD) and its receptor ACE2. The naturally occurring Q498Y substitution, which is present in currently circulating SARS‐CoV‐2 variants, has drawn the attention of several investigations. While computational predictions and in vitro binding studies suggest that Q498Y increases the binding affinity of the spike protein for ACE2, experimental in vivo models of infection have shown that a triple mutant carrying the Q498Y replacement is fatal in mice. To accurately characterize the binding kinetics of the RBD Q498Y–ACE2 interaction, biolayer interferometry analyses were performed. A significant enhancement of the RBD–ACE2 binding affinity relative to a reference SARS‐CoV‐2 variant of concern carrying three simultaneous replacements was observed. In addition, the RBD Q498Y mutant bound to ACE2 was crystallized. Compared with the structure of its wild‐type counterpart, the RBD Q498Y–ACE2 complex reveals the conservation of major hydrogen‐bond interactions and a more populated, nonpolar set of contacts mediated by the bulky side chain of Tyr498 that collectively lead to this increase in binding affinity. In summary, these studies contribute to a deeper understanding of the impact of a relevant mutation present in currently circulating SARS‐CoV‐2 variants which might lead to stronger host–pathogen interactions. [ FROM AUTHOR] Copyright of Acta Crystallographica: Section D, Structural Biology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

4.
Journal of Kerman University of Medical Sciences ; 29(4):368-377, 2022.
Article in English | EMBASE | ID: covidwho-2010569

ABSTRACT

Background: The COVID-19 pandemic is a red alarm for global health, so researchers around the world are working on it to design an effective vaccine against it. Protein is one of the candidates for vaccine development which plays an important role in virus pathogenesis. Accordingly, this study was done to evaluate the critical characteristic of this protein as a vaccine candidate using in-silico analysis. Methods: The sequence of SARS-CoV-2-associated E protein was recruited from NCBI and subjected to the IEDB software to evaluate the most potent epitopes. The capacity of the interactions of HLA-I and HLA-II molecules with selective peptides was studied using IEBD tool kit. The E protein sequence was subjected to B cell and T cell tests to realize the most promising peptides that could act as COVID-19 vaccine. Results: Among the tested peptides for the T cell-test, this study found two interesting epitopes: VSEETGTLI and LTALRLCAY that exhibit high binding affinity as a strong indicator to HLA-I and HLA-II alleles together. The results of the analysis demonstrated that some epitopes in the E protein have a relatively higher immunogenicity score based on interaction with HLA-II, such as SEETGTLIVNSVLLF, TLIVNSVLLFLAFVV, LAFVVFLLVTLAILT, LAILTALRLCAYCCN, and SVLLFLAFVVFLLVT. Furthermore, two sequences (FVSEET and PSFYVYSRVKNLNSSRVP) were reported as the selective linear epitopes for B cell, on the surface of SARS-CoV-2 E protein and being Immunogenic. Conclusion: Since E protein can stimulate favorable immune responses, T and B-cell responses, its evaluation in patients with COVID-19 is of a great importance.

5.
Journal of chemical information and modeling ; 2022.
Article in English | MEDLINE | ID: covidwho-2008239

ABSTRACT

Five major variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged and posed challenges in controlling the pandemic. Among them, the current dominant variant, viz., Omicron, has raised serious concerns about its infectiousness and antibody neutralization. However, few studies pay attention to the effect of the mutations on the dynamic interaction network of Omicron S protein trimers binding to the host angiotensin-converting enzyme 2 (ACE2). In this study, we conducted molecular dynamics (MD) simulations and enzyme linked immunosorbent assay (ELISA) to explore the binding strength and mechanism of wild type (WT), Delta, and Omicron S protein trimers to ACE2. The results showed that the binding capacities of both the two variants' S protein trimers to ACE2 are enhanced in varying degrees, indicating possibly higher cell infectiousness. Energy decomposition and protein-protein interaction network analysis suggested that both the mutational and conserved sites make effects on the increase in the overall affinity through a variety of interactions. The experimentally determined KD values by biolayer interferometry (BLI) and the predicted binding free energies of the RBDs of Delta and Omicron to mAb HLX70 revealed that the two variants may have the high risk of immune evasion from the mAb. These results are not only helpful in understanding the binding strength and mechanism of S protein trimer-ACE2 but also beneficial for drug, especially for antibody development.

6.
Journal of chemical information and modeling ; 2022.
Article in English | MEDLINE | ID: covidwho-2008238

ABSTRACT

Protein-protein interactions (PPIs) are involved in almost all biological processes in the cell. Understanding protein-protein interactions holds the key for the understanding of biological functions, diseases and the development of therapeutics. Recently, artificial intelligence (AI) models have demonstrated great power in PPIs. However, a key issue for all AI-based PPI models is efficient molecular representations and featurization. Here, we propose Hom-complex-based PPI representation, and Hom-complex-based machine learning models for the prediction of PPI binding affinity changes upon mutation, for the first time. In our model, various Hom complexes Hom(G1, G) can be generated for the graph representation G of protein-protein complex by using different graphs G1, which reveal G1-related inner connections within the graph representation G of protein-protein complex. Further, for a specific graph G1, a series of nested Hom complexes are generated to give a multiscale characterization of the PPIs. Its persistent homology and persistent Euler characteristic are used as molecular descriptors and further combined with the machine learning model, in particular, gradient boosting tree (GBT). We systematically test our model on the two most-commonly used data sets, that is, SKEMPI and AB-Bind. It has been found that our model outperforms all the existing models as far as we know, which demonstrates the great potential of our model for the analysis of PPIs. Our model can be used for the analysis and design of efficient antibodies for SARS-CoV-2.

7.
International Journal of High Performance Computing Applications ; 2022.
Article in English | Web of Science | ID: covidwho-2005565

ABSTRACT

As a theoretically rigorous and accurate method, FEP-ABFE (Free Energy Perturbation-Absolute Binding Free Energy) calculations showed great potential in drug discovery, but its practical application was difficult due to high computational cost. To rapidly discover antiviral drugs targeting SARS-CoV-2 M- pro and TMPRSS2, we performed FEP-ABFE-based virtual screening for similar to 12,000 protein-ligand binding systems on a new generation of Tianhe supercomputer. A task management tool was specifically developed for automating the whole process involving more than 500,000 MD tasks. In further experimental validation, 50 out of 98 tested compounds showed significant inhibitory activity towards M- pro , and one representative inhibitor, dipyridamole, showed remarkable outcomes in subsequent clinical trials. This work not only demonstrates the potential of FEP-ABFE in drug discovery but also provides an excellent starting point for further development of anti-SARS-CoV-2 drugs. Besides, similar to 500 TB of data generated in this work will also accelerate the further development of FEP-related methods.

8.
Virology ; 575:36-42, 2022.
Article in English | ScienceDirect | ID: covidwho-2004599

ABSTRACT

All processes in nature are driven by negative Gibbs energy. Gibbs energy is used by various viruses and their strains to hijack host cell metabolic machinery. The analysis was made by using the atom counting method to obtain elemental compositions and Gibbs energy of growth of the BA.2 strain of SARS-CoV-2. Moreover, Gibbs energy of binding was determined for the BA.2 strain. The properties of BA.2 were compared to those of Hu-1, Delta and Omicron strains. It is concluded that SARS-CoV-2 has evolved by making its Gibbs energy of binding more negative. Hence, it seems that the change in Gibbs energy of binding plays the major role in SARS-CoV-2 evolution. Therefore, Gibbs energy difference between various strains represents the possible mechanism of Darwinian evolution of viruses. In particular, a virus evolves through mutations, resulting in change in information content, elemental composition, increase in infectivity and decrease in pathogenicity.

9.
Biochemical and Biophysical Research Communications ; 2022.
Article in English | ScienceDirect | ID: covidwho-1996029

ABSTRACT

Recent times witnessed an upsurge in the number of COVID19 cases which is primarily attributed to the emergence of several omicron variants, although there is substantial population vaccination coverage across the globe. Currently, many therapeutic antibodies have been approved for emergency usage. The present study critically evaluates the effect of mutations observed in several omicron variants on the binding affinities of different classes of RBD-specific antibodies using a combined approach of immunoinformatics and binding free energy calculations. Our binding affinity data clearly show that omicron variants achieve antibody escape abilities by incorporating mutations at the immunogenic hotspot residues for each specific class of antibody. K417 N and Y505H point mutations are primarily accountable for the loss of class I antibody binding affinities. The K417  N/Q493 R/Q498 R/Y505H combined mutant significantly reduces binding affinities for all the class I antibodies. E484A single mutation, on the other hand, drastically reduces binding affinities for most of the class II antibodies. E484A and E484 A/Q493R double mutations cause a 33–38% reduction in binding affinity for the approved therapeutic monoclonal antibodies. The Q498R RBD mutation observed across all the omicron variants can reduce ∼12% binding affinity for REGN10987, a class III therapeutic antibody, and the L452 R/Q498R double mutation causes a ∼6% decrease in binding affinities for another class III therapeutic antibody, LY-CoV1404. Our data suggest that achieving the immune evasion abilities appears to be the selection pressure behind the emergence of omicron variants.

10.
FEBS Open Bio ; 12:231, 2022.
Article in English | EMBASE | ID: covidwho-1976664

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 5 million people and is causing a devastating social and economic impact all over the world. The rise of new variants represents a difficult challenge due to the loss of vaccine and natural immunity, and increased transmissibility. These variants contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes, via its receptor binding domain (RBD) that binds to angiotensin-converting enzyme 2 (ACE2). To understand the effect of RBD mutations, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis is limited since it ignores the conformational dynamics of the RBD itself. Observing that some variants mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect RBD conformational dynamics. To test this, we performed long atomistic molecular dynamics simulations to investigate the structural dynamics of wt RBD, and that of three variants (alpha, beta and delta). Our results show that in solution, wt RBD presents two distinct conformations: an 'open' conformation where it is free to bind ACE2;and a 'closed' conformation, where the RBM ridge blocks the binding surface. The alpha and beta variants significantly impact the open/closed equilibrium, shifting it towards the open conformation by roughly 20%. This shift likely increases ACE2 binding affinity. In the delta variant RBD simulations, the closed conformation was never observed. Instead, the system alternated between the before mentioned open conformation and an alternative 'reversed' one, with a significantly changed orientation of the RBMridge flanking the RBD. These results support the hypothesis that variants impact RBD conformational dynamics in a direction that simultaneously promotes efficient binding to ACE2 and antibody escape.

11.
FEBS Open Bio ; 12:260-261, 2022.
Article in English | EMBASE | ID: covidwho-1976661

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic, which escalated into a global pandemic in early 2020, accounting for more than 400 million infections and more than 6 million confirmed deaths worldwide (as of 2022/03/10). The SARS-CoV-2 mechanism of transmission and infection involves the binding of the virus to the angiotensin-converting enzyme 2 (ACE2) host receptor through the receptor-binding domain (RBD) of the spike (S) protein. The RBD is a privileged target of our immune system and antiviral therapies. Throughout last year multiple vaccines and new therapeutics against SARS-CoV-2 have been developed. However, their effectiveness is challenged by the continuous evolution of SARS-CoV-2, accompanying the origin and spread of new variants of concern (VOC): Alpha, Beta, Gamma, Delta, and recently, Omicron. Among the reported mutations in the VOC S proteins, several are specific to the RBD, which are associated with higher transmissibility or the ability to escape the immune response of previously infected patients. (Previously published in: Greaney, A.J. et al. (2021) Cell Host Microbe 29,44- 57). In late 2021, the newly SARS-CoV-2 Omicron VOC raised considerable global concern due to the presence of more than 30 mutations in the S protein, 15 of which occur in the RBD (Previously published in: Mannar D et al. (2022) Science 375,760-764). Here we investigated the impact of the VOC RBD mutations on its interaction with ACE2, with a major focus on the Omicron RBD, by performing microsecond molecular dynamics (MD) simulations of this complex. Our analysis of the binding and structural dynamics of these mutations provided a detailed characterization of the binding mode between the VOC RBDs and the receptor. This allowed us to understand the role of key residues in the VOC RBD-ACE2 interface and the effect of specific substitutions on the binding affinity via the establishment of new inter-protein contacts.

13.
Letters in Drug Design and Discovery ; 19(11):996-1006, 2022.
Article in English | EMBASE | ID: covidwho-1968943

ABSTRACT

Background: The 2019 novel coronavirus disease (COVID-19) has caused a global health catastrophe by affecting the human population around the globe. Unfortunately, there is no specific medi-cation or treatment currently available for COVID-19. Objective: It is extremely important to find effective drug treatment in order to put an end to this pandemic period and return to normal daily life. In this context and considering the urgency, rather than focusing on the discovery of novel compounds, it is critical to explore the effects of existing herbal agents with proven antiviral properties on the virus. Methods: Molecular docking studies were carried out employing three different methods, Glide extra precision (XP) docking, induced fit docking (IFD), and molecular mechanics/generalized born surface area (MM/GBSA), to determine the potential antiviral and antibacterial effects of 58 phytochemicals present in Rosmarinus officinalis, Thymbra spicata, Satureja thymbra, and Stachys lavandulifolia plants against the main protease (Mpro) and angiotensin-converting enzyme 2 (ACE2) enzymes. Results: 7 compounds stood out among all the molecules, showing very high binding affinities. Accord-ing to our findings, the substances chlorogenic acid, rosmarinic acid, and rosmanol exhibited extremely significant binding affinities for both Mpro and ACE2 enzymes. Furthermore, carnosic acid and alpha-cadinol showed potent anti-Mpro activity, whereas caffeic acid and carvacrol exhibited promising anti-ACE2 activity. Conclusion: Chlorogenic acid, rosmarinic acid, rosmanol, carnosic acid, alpha-cadinol, caffeic acid, and carvacrol compounds have been shown to be powerful anti-SARS-CoV-2 agents in docking simulations against Mpro and ACE2 enzymes, as well as ADME investigations.

14.
Zeitschrift fur Phytotherapie ; 43:S46, 2022.
Article in English | EMBASE | ID: covidwho-1967698

ABSTRACT

Introduction SARS-CoV-2 variants of concern (VOCs) represent an alarming threat as they may escape vaccination effectiveness. Broad-spectrum antivirals could complement and further enhance preventive benefits achieved through SARS-CoV-2 vaccination campaigns. Aim Testing the antiviral activity of Echinacea purpurea against VOCs and exploring underlying modes-of-action. Method A hydroethanolic extract of freshly harvested E. purpurea herb and roots (Echinaforce®, EF extract) was tested to inhibit infection of VOCs B1.1.7 (alpha), B.1.351.1 (beta), P.1 (gamma), B1.617.2 (delta), AV.1 (Scottish) and B1.525 (eta). Molecular dynamics (MD) were used to study interaction of EF phytochemical markers with known pharmacological viral and host cell targets. Results EF broadly inhibited propagation of all tested SARS-CoV-2 VOCs at EC50 < 12.0 ;jg/ml. Treatment of epithelial cells with 20 jg/ml EF prevented sequential infection with SARS-CoV-2 (Hu-1). MD analyses showed for alkylamides, caftaric acid and feruoyl-tartaric constant binding affinity to spike proteins of all VOCs and to TMPRSS-2, a serine protease required for virus endocytosis. Conclusion EF extract exhibits virucidal activity against all tested SARS-CoV-2 VOCs and protects epithelial cells from infection.

15.
Front Immunol ; 13: 893247, 2022.
Article in English | MEDLINE | ID: covidwho-1957158

ABSTRACT

TCR-epitope pair binding is the key component for T cell regulation. The ability to predict whether a given pair binds is fundamental to understanding the underlying biology of the binding mechanism as well as developing T-cell mediated immunotherapy approaches. The advent of large-scale public databases containing TCR-epitope binding pairs enabled the recent development of computational prediction methods for TCR-epitope binding. However, the number of epitopes reported along with binding TCRs is far too small, resulting in poor out-of-sample performance for unseen epitopes. In order to address this issue, we present our model ATM-TCR which uses a multi-head self-attention mechanism to capture biological contextual information and improve generalization performance. Additionally, we present a novel application of the attention map from our model to improve out-of-sample performance by demonstrating on recent SARS-CoV-2 data.


Subject(s)
Epitopes, T-Lymphocyte , Receptors, Antigen, T-Cell , Computational Biology , Epitopes, T-Lymphocyte/metabolism , Humans , Protein Binding , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2
16.
Indian Journal of Pharmaceutical Sciences ; 84(3):617-630, 2022.
Article in English | EMBASE | ID: covidwho-1957666

ABSTRACT

Drug repositioning may be a promising way to find potential therapies against coronavirus disease 2019. Although chloroquine and hydroxychloroquine showed controversial results against the coronavirus disease 2019 disease, the potential common and diverging mechanisms of action are not reported and need to be dissected for better understanding them. An integrated strategy was proposed to systematically decipher the common and diverging aspects of mechanism of chloroquine and hydroxychloroquine against coronavirus disease 2019-disease network based on network pharmacology and in silico molecular docking. Potential targets of the two drugs and coronavirus disease 2019 related genes were collected from online public databases. Target function enrichment analysis, tissue enrichment maps and molecular docking analysis were carried out to facilitate the systematic understanding of common and diverging mechanisms of the two drugs. Our results showed that 51 chloroquine targets and 47 hydroxychloroquine targets were associated with coronavirus disease 2019. The core targets include tumor necrosis factor, glyceraldehyde 3-phosphate dehydrogenase, lymphocyte-specific protein-tyrosine kinase, beta-2 microglobulin, nuclear receptor coactivator 1, peroxisome proliferator-activated receptor gamma and glutathione disulfide reductase. Both chloroquine and hydroxychloroquine had good binding affinity towards tumor necrosis factor (affinity=-8.6 and -8.4 kcal/mol, respectively) and glyceraldehyde 3-phosphate dehydrogenase (-7.5 and -7.5 kcal/mol). Chloroquine and hydroxychloroquine both had good affinity with angiotensin-converting enzyme 2, 3-chymotrypsin-like protease and transmembrane serine protease 2. However, hydroxychloroquine manifested better binding affinity with the three proteins comparing with that of chloroquine. Chloroquine and hydroxychloroquine could have potential to inhibit over-activated immunity and inflammation. The potential tissue-specific regulation of the two drugs against severe acute respiratory syndrome coronavirus 2 infection may related with the lung, liver, brain, placenta, kidney, blood, eye, etc. In conclusion, our data systematically demonstrated chloroquine and hydroxychloroquine may have potential regulatory effects on coronavirus disease 2019 disease network, which may affect multiple organs, protein targets and pathways. Routine measurements of the chloroquine and hydroxychloroquine blood concentrations and tailored therapy regimen may be essential. But, further rigorous and high quality randomized controlled clinical trials are warranted to validate the antiviral effects of chloroquine and hydroxychloroquine against severe acute respiratory syndrome coronavirus 2. Our proposed strategy could facilitate the drug repurposing efforts for coronavirus disease 2019 treatment.

17.
Pharmacognosy Journal ; 14(3):604-609, 2022.
Article in English | EMBASE | ID: covidwho-1957552

ABSTRACT

The global pandemic of coronavirus disease is still widely spread across the world causing catastrophic effect in both human life and global economy. By the end of year 2021, it has caused a total of 5.437.636 deaths across the world. Indonesia has rich plant biodiversity including medicinal plants that may be used for combating the virus. One of the commonly used medicinal plants comes from Allium species and it has been proved to have antiviral activity. Conducting an in silico study, we screened bioactive compounds that came from Allium sativum to fight against coronavirus through the inhibition of 3CL-Pro, one of the major protease that have an active role for viral replication. Molecular docking of compounds from Allium sativum to 3CL-Pro resulting in the discovery of 5 compounds that have the best binding affinity to 3CL-Pro, which are squalene, 1,4-dihydro-2,3-benzoxathiin 3-oxide, 1,2,3-propanetriyl ester, trans-13-octadecenoic acid and methyl-11-hexadecenoate with binding affinity of -7, -6.5, -5.9, -5.7 and -5.6 kcal/mol, respectively. It is very likely that these compounds can be candidates for therapeutic agents and these candidates need to be studied further.

18.
Brief Funct Genomics ; 2022 Jul 18.
Article in English | MEDLINE | ID: covidwho-1948161

ABSTRACT

Most pathogens mutate and evolve over time to escape immune and drug pressure. To achieve this, they alter specific hotspot residues in their intracellular proteins to render the targeted drug(s) ineffective and develop resistance. Such hotspot residues may be located as a cluster or uniformly as a signature of adaptation in a protein. Identifying the hotspots and signatures is extremely important to comprehensively understand the disease pathogenesis and rapidly develop next-generation therapeutics. As experimental methods are time-consuming and often cumbersome, there is a need to develop efficient computational protocols and adequately utilize them. To address this issue, we present a unique computational protein design protocol that identifies hotspot residues, resistance mutations and signatures of adaptation in a pathogen's protein against a bound drug. Using the protocol, the binding affinity between the designed mutants and drug is computed quickly, which offers predictions for comparison with biophysical experiments. The applicability and accuracy of the protocol are shown using case studies of a few protein-drug complexes. As a validation, resistance mutations in severe acute respiratory syndrome coronavirus 2 main protease (Mpro) against narlaprevir (an inhibitor of hepatitis C NS3/4A serine protease) are identified. Notably, a detailed methodology and description of the working principles of the protocol are presented. In conclusion, our protocol will assist in providing a first-hand explanation of adaptation, hotspot-residue variations and surveillance of evolving resistance mutations in a pathogenic protein.

19.
Dhaka University Journal of Pharmaceutical Sciences ; 21(1):1-13, 2022.
Article in English | EMBASE | ID: covidwho-1928409

ABSTRACT

The coronavirus pandemic of 2019 (COVID-19) has adversely affected public health and the socioeconomic situation worldwide. Although there is no therapeutic drug to treat COVID, several treatment options are being considered to alleviate symptoms. Hence, researches on prophylactic treatment for COVID are being encouraged. Searching natural products is a rational strategy since it has served as a valuable source of lead compounds in drug discovery. In this study, three machine learning approaches, including Support Vector Machine (SVM), Random Forest (RF) and Gradient Boosting Machine (GBM), have been used to develop the classification model. The molecular docking was performed on AutoDock vina. Further, molecular dynamics (MD) simulation of the potential inhibitors was conducted using the AmberTools package. The accuracy for SVM, RF and GBM was found to be 60.45 %, 63.43 % and 64.93 %, respectively. Further, the model has demonstrated specificity range of 41.67 % to 50.00 % and sensitivity range of 74.32 % to 79.73 %. Application of the model on the NuBBE database, a repository of natural compounds, led us to identify 322 unique natural compounds, likely possessing anti-SARS-CoV-2activity. Further, molecular docking study has yielded three flavonoids and one lignoid compounds with comparable binding affinities to the standard compound. In addition, MD showed that these compounds form stable complexes with different magnitude of binding energy. The in silico investigations suggest that these four compounds likely demonstrate their anti-SARS-CoV-2activity by inhibiting the main protease enzyme. Our developed and validated in silico high-throughput investigations may assist in identifying and developing antiviral drug-like compounds from natural sources.

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