Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 109
Filter
1.
Tzu Chi Med J ; 34(3): 276-286, 2022.
Article in English | MEDLINE | ID: covidwho-1957522

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic is currently the most serious public health threat faced by mankind. Thus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, is being intensively investigated. Several vaccines are now available for clinical use. However, owing to the highly mutated nature of RNA viruses, the SARS-CoV-2 is changing at a rapid speed. Breakthrough infections by SARS-CoV-2 variants have been seen in vaccinated individuals. As a result, effective therapeutics for treating COVID-19 patients is urgently required. With the advance of computer technology, computational methods have become increasingly powerful in the biomedical research and pharmaceutical drug discovery. The applications of these techniques have largely reduced the costs and simplified processes of pharmaceutical drug developments. Intensive and extensive studies on SARS-CoV-2 proteins have been carried out and three-dimensional structures of the major SARS-CoV-2 proteins have been resolved and deposited in the Protein Data Bank. These structures provide the foundations for drug discovery and design using the structure-based computations, such as molecular docking and molecular dynamics simulations. In this review, introduction to the applications of computational methods in the discovery and design of novel drugs and repurposing of existing drugs for the treatments of COVID-19 is given. The examples of computer-aided investigations and screening of COVID-19 effective therapeutic compounds, functional peptides, as well as effective molecules from the herb medicines are discussed.

2.
Front Mol Biosci ; 9: 898874, 2022.
Article in English | MEDLINE | ID: covidwho-1952441

ABSTRACT

The ongoing pandemic coronavirus disease (COVID-19) caused by a novel corona virus, namely, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has had a major impact on global public health. COVID-19 cases continue to increase across the globe with high mortality rates in immunocompromised patients. There is still a pressing demand for drug discovery and vaccine development against this highly contagious disease. To design and develop antiviral drugs against COVID-19, the main protease (Mpro) has emerged as one of the important drug targets. In this context, the present work explored Jadwar (Delphinium denudatum)-derived natural alkaloids as potential inhibitors against Mpro of SARS-CoV-2 by employing a combination of molecular docking and molecular dynamic simulation-based methods. Molecular docking and interaction profile analysis revealed strong binding on the Mpro functional domain with four natural alkaloids viz. panicutine (-7.4 kcal/mol), vilmorrianone (-7.0 kcal/mol), denudatine (-6.0 kcal/mol), and condelphine (-5.9 kcal/mol). The molecular docking results evaluated by using the MD simulations on 200 nanoseconds confirmed highly stable interactions of these compounds with the Mpro. Additionally, mechanics/generalized Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations also affirmed the docking results. Natural alkaloids explored in the present study possess the essential drug-likeness properties, namely, absorption, distribution, metabolism, and excretion (ADME), and are in accordance with Lipinski's rule of five. The results of this study suggest that these four bioactive molecules, namely, condelphine, denudatine, panicutine, and vilmorrianone, might be effective candidates against COVID-19 and can be further investigated using a number of experimental methods.

3.
Comput Struct Biotechnol J ; 20: 2309-2321, 2022.
Article in English | MEDLINE | ID: covidwho-1944736

ABSTRACT

Fentanyl and its analogs are selective agonists of the µ-opioid receptor (MOR). Among novel synthetic opioids (NSOs), they dominate the recreational drug market and are the main culprits for the opioid crisis, which has been exacerbated by the COVID-19 pandemic. By taking advantage of the crystal structures of the MOR, several groups have investigated the binding mechanism of fentanyl, but have not reached a consensus, in terms of both the binding orientation and the fentanyl conformation. Thus, the binding mechanism of fentanyl at the MOR remains an unsolved and challenging question. Here, we carried out a systematic computational study to investigate the preferred fentanyl conformations, and how these conformations are being accommodated in the MOR binding pocket. We characterized the free energy landscape of fentanyl conformations with metadynamics simulations, and compared and evaluated several possible fentanyl binding conditions in the MOR with long-timescale molecular dynamics simulations. Our results indicate that the most preferred binding pose in the MOR binding pocket corresponds well with the global minimum on the energy landscape of fentanyl in the absence of the receptor, while the energy landscape can be reconfigured by modifying the fentanyl scaffold. The interactions with the receptor may stabilize a slightly unfavored fentanyl conformation in an alternative binding pose. By extending similar investigations to fentanyl analogs, our findings establish a structure-activity relationship of fentanyl binding at the MOR. In addition to providing a structural basis to understand the potential toxicity of the emerging NSOs, such insights will contribute to developing new, safer analgesics.

4.
Int J Mol Sci ; 21(16)2020 Aug 06.
Article in English | MEDLINE | ID: covidwho-1934101

ABSTRACT

The recently discovered 340-cavity in influenza neuraminidase (NA) N6 and N7 subtypes has introduced new possibilities for rational structure-based drug design. However, the plasticity of the 340-loop (residues 342-347) and the role of the 340-loop in NA activity and substrate binding have not been deeply exploited. Here, we investigate the mechanism of 340-cavity formation and demonstrate for the first time that seven of nine NA subtypes are able to adopt an open 340-cavity over 1.8 µs total molecular dynamics simulation time. The finding that the 340-loop plays a role in the sialic acid binding pathway suggests that the 340-cavity can function as a druggable pocket. Comparing the open and closed conformations of the 340-loop, the side chain orientation of residue 344 was found to govern the formation of the 340-cavity. Additionally, the conserved calcium ion was found to substantially influence the stability of the 340-loop. Our study provides dynamical evidence supporting the 340-cavity as a druggable hotspot at the atomic level and offers new structural insight in designing antiviral drugs.


Subject(s)
Antiviral Agents/pharmacology , Drug Development , Neuraminidase/chemistry , Orthomyxoviridae/enzymology , Binding Sites , Calcium/chemistry , Ions , Models, Molecular , Molecular Dynamics Simulation , N-Acetylneuraminic Acid/chemistry , Principal Component Analysis , Protein Structure, Secondary , Thermodynamics
5.
Int J Mol Sci ; 23(13)2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1934134

ABSTRACT

Chia seed peptides (CSP) can be a source of multifunctional biopeptides to treat non-communicable diseases. However, interactions and binding affinity involved in targeting specific receptors remains unexplored. In this study, molecular simulation techniques were used as virtual screening of CSP to determine drug-like candidates using a multi-target-directed ligand approach. CSP fraction with the best bioactivities in vitro was sequenced. Then, a prediction model was built using physicochemical descriptors (hydrophobicity, hydrophilicity, intestinal stability, antiangiogenic, antihypertensive, and anti-inflammatory) to calculate potential scores and rank possible biopeptides. Furthermore, molecular dynamics simulations (MDS) and ensemble molecular docking analysis were carried out using four human protein targets (ACE, angiotensin converting enzyme; VEGF, vascular endothelial growth factor; GLUC, glucocorticoid and MINC, mineralocorticoid receptors). Five known-sequence peptides (NNVFYPF, FNIVFPG, SRPWPIDY, QLQRWFR, GSRFDWTR) and five de novo peptides (DFKF, DLRF, FKAF, FRSF, QFRF) had the lowest energy score and higher affinity for ACE and VEGF. The therapeutic effects of these selected peptides can be related to the inhibition of the enzymes involved in angiogenesis and hypertension, due to formation of stable complexes with VEGF and ACE binding sites, respectively. The application of MDS is a good resource for identifying bioactive peptides for future experimental validation.


Subject(s)
Salvia hispanica , Salvia , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptides/chemistry , Plant Extracts , Salvia/chemistry , Vascular Endothelial Growth Factor A
6.
Sci Afr ; 17: e01279, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1926887

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is one of the major health threats the world has experienced. In order to stem the tide of the virus and its associated disease, rapid efforts have been dedicated to identifying credible anti-SARS-CoV-2 drugs. This study forms part of the continuing efforts to develop anti-SARS-CoV-2 molecules and employed a computational structure-activity relationship approach with emphasis on 99 plant secondary metabolites from eight selected African medicinal plants with proven therapeutic benefits against respiratory diseases focusing on the viral protein targets [Spike protein (Sgp), Main protease (Mpro), and RNA-dependent RNA polymerase (RdRp)]. The results of the molecular dynamics simulation of the best docked compounds presented as binding free energy revealed that three compounds each against the Sgp (VBS, COG and ABA), and Mpro (COR, QOR and ABG) had higher and better affinity for the proteins than the respective reference drugs, cefoperazone (CSP) and Nelfinavir (NEF), while four compounds (HDG, VBS, COR and KOR) had higher and favorable binding affinity towards RdRp than the reference standard, ramdesivir (RDS). Analysis of interaction with the receptor binding domain amino acid residues of Sgp showed that VBS had the highest number of interactions (17) relative to 14 and 13 for COG and ABA, respectively. For Mpro, COR showed interactions with catalytic dyad residues (His172 and Cys145). Compared to RDS, COR, HDG, VBS and KOR formed 19, 18, 17 and 12 H-bond and Van der Waal bonds, respectively, with RdRp. Furthermore, structural examination of the three proteins after binding to the lead compounds revealed that the compounds formed stable complexes. These observations suggest that the identified compounds might be beneficial in the fight against COVID-19 and are suggested for further in vitro and in vivo experimental validation.

7.
J Mol Graph Model ; 116: 108260, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1914639

ABSTRACT

The SARS-CoV-2 is an RNA-based virus and the most vital step of its survival is the attachment to hACE2 through its spike protein. Although SARS-CoV-2 has the ability to maintain high accurate replication and it can be accepted as a low mutation risked virus, it already showed more than nine thousand mutations in spike protein, of which 44 mutations are located within a 3.2 Å interacting distance from the hACE2 receptor. Mutations on spike protein, N501Y and N501T raised serious concerns for higher transmissibility and resistance towards current vaccines. In the current study, the mutational outcomes of N501Y and N501T on the hACE2-SARS CoV-2 spike protein complexation were analyzed by employing all-atom classic molecular dynamics (MD) simulations. These simulations revealed that both N501Y and N501T mutations increased the binding strength of spike protein to the host hACE2, predicted by binding free energy analysis via MM/GBSA rescoring scheme. This study highlights the importance of energy-based analysis for identifying mutational outcomes and will shed light on handling long-term and effective treatment strategies including repurposing anti-viral drugs, anti-SARS-CoV-2 antibodies, vaccines, and antisense based-therapies.

8.
Struct Chem ; : 1-21, 2022 Jul 04.
Article in English | MEDLINE | ID: covidwho-1913998

ABSTRACT

COVID-19 disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) has resulted in tremendous loss of lives across the world and is continuing to do so. Extensive work is under progress to develop inhibitors which can prevent the disease by arresting the virus in its life cycle. One such way is by targeting the main protease of the virus which is crucial for the cleavage and conversion of polyproteins into functional units of polypeptides. In this endeavor, our effort was to identify hit molecule inhibitors for SARS-CoV2 main protease using fragment-based drug discovery (FBDD), based on the available crystal structure of chromene-based inhibitor (PDB_ID: 6M2N). The designed molecules were validated by molecular docking and molecular dynamics simulations. The stability of the complexes was further assessed by calculating their binding free energies, normal mode analysis, mechanical stiffness, and principal component analysis. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-01995-z.

9.
Comput Biol Med ; 147: 105735, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1906919

ABSTRACT

Since the new variant of SARS-CoV-2, Omicron (BA.1) has raised serious concerns, it is important to investigate the effects of mutations in the NTD and RBD domains of the spike protein for the development of COVID-19 vaccines. In this study, computational analysis of the Wuhan and Omicron NTDs and RBDs in their unbound and bound states to mAb 4A8 and ACE2 were performed. In addition, the interaction of NTD with antibody and RBD with ACE2 were evaluated in the presence of long glycans. The results show that long glycans at the surface of NTDs can reduce the accessibility of protein epitopes, thereby reducing binding efficiency and neutralizing potency of specific antibodies. Also, our findings indicate that the existence of the long glycans result in increased stability and enhanced affinity of the RBD to ACE2 in the Wuhan and Omicron variant. Key residues that play an important role in increasing the structural stability of the protein were identified using RIN analysis and in the state of interaction with mAb 4A8 and ACE2 through per-residue decomposition analysis. Further, the results of the free energy binding calculation using MM/GBSA method show that the Omicron variant has a higher infectivity than the Wuhan. This study provides a better understanding of the structural changes in the spike protein and can be useful for the development of novel therapeutics.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , COVID-19 Vaccines , Humans , Mutation , Peptidyl-Dipeptidase A/chemistry , Protein Binding , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
10.
Comput Biol Chem ; 99: 107721, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1906916

ABSTRACT

Papain like protease (PLpro) is a cysteine protease from the coronaviridae family of viruses. Coronaviruses possess a positive sense, single-strand RNA, leading to the translation of two viral polypeptides containing viral structural, non-structural and accessory proteins. PLpro is responsible for the cleavage of nsp1-3 from the viral polypeptide. PLpro also possesses deubiquitinating and deISGlyating activity, which sequesters the virus from the host's immune system. This indispensable attribute of PLpro makes it a protein of interest as a drug target. The present study aims to analyze the structural influences of ligand binding on PLpro. First, PLpro was screened against the ZINC-in-trials library, from which four lead compounds were identified based on estimated binding affinity and interaction patterns. Next, based on molecular docking results, ZINC000000596945, ZINC000064033452 and VIR251 (control molecule) were subjected to molecular dynamics simulation. The study evaluated global and essential dynamics analyses utilising principal component analyses, dynamic cross-correlation matrix, free energy landscape and time-dependant essential dynamics to predict the structural changes observed in PLpro upon ligand binding in a simulated environment. The MM/PBSA-based binding free energy calculations of the two selected molecules, ZINC000000596945 (-41.23 ± 3.70 kcal/mol) and ZINC000064033452 (-25.10 ± 2.65 kcal/mol), displayed significant values which delineate them as potential inhibitors of PLpro from SARS-CoV-2.


Subject(s)
COVID-19 , Papain , Coronavirus Papain-Like Proteases , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Papain/chemistry , Papain/genetics , Papain/metabolism , Peptide Hydrolases/genetics , Peptide Hydrolases/metabolism , SARS-CoV-2
11.
Cells ; 11(12)2022 06 14.
Article in English | MEDLINE | ID: covidwho-1896810

ABSTRACT

The new coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been reported and spread globally. There is an urgent need to take urgent measures to treat and prevent further infection of this virus. Here, we use virtual drug screening to establish pharmacophore groups and analyze the ACE2 binding site of the spike protein with the ZINC drug database and DrugBank database by molecular docking and molecular dynamics simulations. Screening results showed that Venetoclax, a treatment drug for chronic lymphocytic leukemia, has a potential ability to bind to the spike protein of SARS-CoV-2. In addition, our in vitro study found that Venetoclax degraded the expression of the spike protein of SARS-CoV-2 through amino acids Q493 and S494 and blocked the interaction with the ACE2 receptor. Our results suggest that Venetoclax is a candidate for clinical prevention and treatment and deserves further research.


Subject(s)
COVID-19 , SARS-CoV-2 , Amino Acids/metabolism , Angiotensin-Converting Enzyme 2 , Bridged Bicyclo Compounds, Heterocyclic , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Spike Glycoprotein, Coronavirus/chemistry , Sulfonamides
12.
Comput Biol Med ; 147: 105758, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1894907

ABSTRACT

BACKGROUND: The vaccines used against SARS-CoV-2 by now have been able to develop some neutralising antibodies in the vaccinated population and their effectiveness has been challenged by the emergence of the new strains with numerous mutations in the spike protein of SARS-CoV-2. Since S protein is the major immunogenic protein of the virus which contains Receptor Binding Domain (RBD) that interacts with the human Angiotensin-Converting Enzyme 2 (ACE2) receptors, any mutations in this region should affect the neutralisation potential of the antibodies leading to the immune evasion. Several variants of concern of the virus have emerged so far, amongst which the most critical are Delta and recently reported Omicron. In this study, we have mapped and reported mutations on the modelled RBD and evaluated binding affinities of various human antibodies with it. METHOD: Docking and molecular dynamics simulation studies have been used to explore the effect of mutations on the structure of RBD and RBD-antibody interaction. RESULTS: These analyses show that the mutations mostly at the interface of a nearby region lower the binding affinity of the antibody by ten to forty percent, with a downfall in the number of interactions formed as a whole. It implies the generation of immune escape variants. CONCLUSIONS: Notable mutations and their effect was characterised that explain the structural basis of antibody efficacy in Delta and a compromised neutralisation effect for the Omicron variant. Thus, our results pave the way for robust vaccine design that can be effective for many variants.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Immune Evasion , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
13.
Biochim Biophys Acta Biomembr ; 1864(10): 183994, 2022 Oct 01.
Article in English | MEDLINE | ID: covidwho-1894808

ABSTRACT

SARS-CoV-2 contains four structural proteins in its genome. These proteins aid in the assembly and budding of new virions at the ER-Golgi intermediate compartment (ERGIC). Current fundamental research efforts largely focus on one of these proteins - the spike (S) protein. Since successful antiviral therapies are likely to target multiple viral components, there is considerable interest in understanding the biophysical role of its other structural proteins, in particular structural membrane proteins. Here, we have focused our efforts on the characterization of the full-length envelope (E) protein from SARS-CoV-2, combining experimental and computational approaches. Recombinant expression of the full-length E protein from SARS-CoV-2 reveals that this membrane protein is capable of independent multimerization, possibly as a tetrameric or smaller species. Fluorescence microscopy shows that the protein localizes intracellularly, and coarse-grained MD simulations indicate it causes bending of the surrounding lipid bilayer, corroborating a potential role for the E protein in viral budding. Although we did not find robust electrophysiological evidence of ion-channel activity, cells transfected with the E protein exhibited reduced intracellular Ca2+, which may further promote viral replication. However, our atomistic MD simulations revealed that previous NMR structures are relatively unstable, and result in models incapable of ion conduction. Our study highlights the importance of using high-resolution structural data obtained from a full-length protein to gain detailed molecular insights, and eventually permitting virtual drug screening.


Subject(s)
COVID-19 , SARS-CoV-2 , Calcium , Humans , Viral Envelope Proteins/chemistry , Virus Assembly
14.
Mol Divers ; 2022 Jun 12.
Article in English | MEDLINE | ID: covidwho-1888948

ABSTRACT

Novel drug compound hunting was carried out for SARS-CoV-2 proteins with low mutation susceptibility. The probability of escape mutation and drug resistance is lower if conserved microbial proteins are targeted by therapeutic drugs. Mutation rate of all SARS-CoV-2 proteins were analyzed via multiple sequence alignment Non-Structural Protein 13 and Non-Structural Protein 16 were selected for the current study due to low mutation rate among viral strains and significant functionality. Cross-species mutation rate analysis for NSP13 and NSP16 showed these are well-conserved proteins among four coronaviral species. Viral helicase inhibitors, identified using literature-mining, were docked against NSP13. Pharmacophore-based screening of 11,375 natural compounds was conducted for NSP16. Stabilities of top compounds inside human body were confirmed via molecular dynamic simulation. ADME properties and LD50 values of the helicase inhibitors and Ambinter natural compounds were analyzed. Compounds against NSP13 showed binding affinities between -10 and -5.9 kcal/mol whereby ivermectin and scutellarein showed highest binding energies of -10 and -9.9 kcal/mol. Docking of 18 hit compounds against NSP16 yielded binding affinities between -8.9 and -4.1 kcal/mol. Hamamelitannin and deacyltunicamycin were the top compounds with binding affinities of -8.9 kcal/mol and -8.4 kcal/mol. The top compounds showed stable ligand-protein interactions in molecular dynamics simulation. The analyses revealed two hit compounds against each targeted protein displaying stable behavior, high binding affinity and molecular interactions. Conversion of these compounds into drugs after in vitro experimentation can become better treatment options to elevate COVID management.

15.
Quantitative Biology ; 9(1):61-72, 2021.
Article in English | ProQuest Central | ID: covidwho-1876232

ABSTRACT

Background: A novel coronavirus (the SARS-CoV-2) has been identified in January 2020 as the causal pathogen for COVID-19 , a pandemic started near the end of 2019. The Angiotensin converting enzyme 2 protein (ACE2) utilized by the SARS-CoV as a receptor was found to facilitate the infection of SARS-CoV-2, initiated by the binding of the spike protein to human ACE2. Methods: Using homology modeling and molecular dynamics (MD) simulation methods, we report here the detailed structure and dynamics of the ACE2 in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Results: The predicted model is highly consistent with the experimentally determined structures, validating the homology modeling results. Besides the binding interface reported in the crystal structures, novel binding poses are revealed from all-atom MD simulations. The simulation data are used to identify critical residues at the complex interface and provide more details about the interactions between the SARS-CoV-2 RBD and human ACE2. Conclusion: Simulations reveal that RBD binds to both open and closed state of ACE2. Two human ACE2 mutants and rat ACE2 are modeled to study the mutation effects on RBD binding to ACE2. The simulations show that the N-terminal helix and the K353 are very important for the tight binding of the complex, the mutants are found to alter the binding modes of the CoV2-RBD to ACE2.

16.
J Mol Struct ; 1265: 133391, 2022 Oct 05.
Article in English | MEDLINE | ID: covidwho-1867596

ABSTRACT

In the fall of 2019, a new type of coronavirus took place in Wuhan city, China, and rapidly spread across the world and urges the scientific community to develop antiviral therapeutic agents. In our effort we have synthesized a new hydrazide derivative, (E)-N'-(1-(4-bromophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propanehydrazide for this purpose because of its potential inhibitory proprieties. The asymmetric unit of the title molecule consists of two independent molecules differing noticeably in conformation. In the crystal, the independent molecules are linked by N-H···O and C-H···O hydrogen bonds and C-H···π(ring) interactions into helical chains extending along the b-axis direction. The chains are further joined by additional C-H···π(ring) interactions into the full 3-D structure. To obtain a structure-activity relationship, the DFT-NBO analysis is performed to study the intrinsic electronic properties of the title compound. Molecular modeling studies were also conducted to examine the binding affinity of the compound for the SARS-CoV-2 main protease enzyme and to determine intermolecular binding interactions. The compound revealed a stable binding mode at the enzyme active pocket with a binding energy value of -8.1 kcal/mol. Further, stable dynamics were revealed for the enzyme-compound complex and reported highly favorable binding energies. The net MMGBSA binding energy of the complex is -37.41 kcal/mol while the net MMPBSA binding energy is -40.5 kcal/mol. Overall, the compound disclosed the strongest bond of ing the main protease enzyme and might be a good lead for further structural optimization.

17.
Comput Struct Biotechnol J ; 20: 1254-1263, 2022.
Article in English | MEDLINE | ID: covidwho-1850917

ABSTRACT

Although COVID-19 has been primarily associated with pneumonia, recent data show that its causative agent, the SARS-CoV-2 coronavirus, can infect many vital organs beyond the lungs, including the heart, kidneys and the brain. The literature agrees that COVID-19 is likely to have long-term mental health effects on infected individuals, which signifies a need to understand the role of the virus in the pathophysiology of brain disorders that is currently unknown and widely debated. Our docking and molecular dynamics simulations show that the affinity of the spike protein from the wild type (WT) and the South African B.1.351 (SA) variant towards MAO enzymes is comparable to that for its ACE2 receptor. This allows for the WT/SA⋅⋅⋅MAO complex formation, which changes MAO affinities for their neurotransmitter substrates, thereby impacting their metabolic conversion and misbalancing their levels. Knowing that this fine regulation is strongly linked with the etiology of various brain pathologies, these results are the first to highlight the possibility that the interference with the brain MAO catalytic activity is responsible for the increased neurodegenerative illnesses following a COVID-19 infection, thus placing a neurobiological link between these two conditions in the spotlight. Since the obtained insight suggests that a more contagious SA variant causes even larger disturbances, and with new and more problematic strains likely emerging in the near future, we firmly advise that the presented prospect of the SARS-CoV-2 induced neurological complications should not be ignored, but rather requires further clinical investigations to achieve an early diagnosis and timely therapeutic interventions.

18.
Nanomaterials (Basel) ; 12(9)2022 Apr 30.
Article in English | MEDLINE | ID: covidwho-1847386

ABSTRACT

Laser interaction with nanoparticles in liquid is the fundamental theoretical basis for many applications but it is still challenging to observe this nanoscale phenomenon within a few nanoseconds in liquid by experiment. The successful implementation of the two-temperature method integrated with molecular dynamics (TTM-MD) in laser interaction with bulk material has shown great potential in providing a panoramic view of the laser interaction with the nanoparticles. However, the current TTM-MD model has to divide the system into cubic cells, which leads to mistakes near the nanoparticle's surface. We introduce the latest model, which performs the TTM-MD on each individual cluster instead of the cubic cells, and its high-performance parallel cluster analysis algorithm to update the cluster size. The cluster-based TTM-MD revealed the nanoparticle formation mechanism of laser fragmentation in liquid (LFL) and facilitated the study of laser fluence's effect on the size distribution. In addition to LFL, this model is promising to be implemented in the laser thermal therapy of tumors, laser melting in liquid (LML), etc. Although cluster-based TTM-MD has proven to be a powerful tool for studying laser interaction with nanoparticles, a few challenges and future developments for the cluster-based TTM-MD, especially the ionization induced by femtosecond, are also discussed.

19.
Carbohydr Res ; 518: 108574, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1821162

ABSTRACT

Can envelope glycans be targeted to stop viral pandemics? Here we address this question by using molecular dynamics simulations to study the binding between 10 synthetic carbohydrate receptors (SCRs) and the 33 N-glycans most commonly found on the surfaces of enveloped viruses, including Zika virus and SARS-CoV-2. Based on association quotients derived from these simulations, we classified the SCRs as weak binders, promiscuous binders, or selective binders. The SCRs almost exclusively associate at the Man3GlcNAc2 core, which is common to all N-glycans, but the binding affinity between the SCR⋅glycan pair depends on the noncovalent interactions between the heterocycle rings and the glycan antennae. Systematic variations in the glycan and SCR structures reveal relationships that could guide the design of SCRs to attain affinity and selectivity towards a chosen envelope glycan target. With these results, envelope glycans, which are currently considered "undruggable", could become viable targets for new therapeutic strategies.


Subject(s)
COVID-19 , Receptors, Artificial , Zika Virus Infection , Zika Virus , Carbohydrates/chemistry , Humans , Molecular Dynamics Simulation , Polysaccharides/chemistry , Receptors, Artificial/chemistry , SARS-CoV-2 , Zika Virus/metabolism
20.
SAR QSAR Environ Res ; 33(5): 341-356, 2022 May.
Article in English | MEDLINE | ID: covidwho-1819655

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) at the end of 2019 affected global health. Its infection agent was called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Wearing a mask, maintaining social distance, and vaccination are effective ways to prevent infection of SARS-CoV-2, but none of them help infected people. Targeting the enzymes of SARS-CoV-2 is an effective way to stop the replication of the virus in infected people and treat COVID-19 patients. SARS-CoV-2 main protease is a therapeutic target which the inhibition of its enzymatic activity prevents from the replication of SARS-CoV-2. A large database of molecules has been searched to identify new inhibitors for SARS-CoV-2 main protease enzyme. At the first step, ligand screening based on similarity search was used to select similar compounds to known SARS-CoV-2 main protease inhibitors. Then molecules with better predicted pharmacokinetic properties were selected. Structure-based virtual screening based on the application of molecular docking and molecular dynamics simulation methods was used to select more effective inhibitors among selected molecules in previous step. Finally two compounds were considered as SARS-CoV-2 main protease inhibitors.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/pharmacology , COVID-19/drug therapy , Computers , Coronavirus 3C Proteases , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/pharmacology , Quantitative Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL