scholarly journals In silico Discovery of a New Potent Inhibitor for Sterol 14-alpha Demethylase as a Promising Antifungal Drug against Aspergillus fumigatus Infection

2021 ◽  
Vol 12 (5) ◽  
pp. 5785-5796
Keyword(s):  
Aspergillus Fumigatus ◽  
In Silico ◽  
Md Simulation ◽  
Potent Inhibitor ◽  
High Specificity ◽  
Md Simulations ◽  
Opportunistic Pathogen ◽  
Amino Acid Residues ◽  
Human Beings ◽  
Heme Group

Aspergillus fumigatus is a dangerous opportunistic pathogen that causes severe consequences for human beings when its conidia are inhaled. Several inhibitory drugs have recently been suggested to eradicate these fungi by inhibiting the cytochrome P450 sterol 14-alpha demethylase B (CYP51B). These drugs are designed to exhibit high specificity to the heme that is incorporated in the active site of this enzyme. Though effective binding with heme can be achieved, administration of these drugs can be accompanied by variable risks to the user’s health. Series of in silico screenings were conducted to find out more eligible drug-like compounds to inhibit CYP51B-heme with fewer side effects on patients. Using stringent ZINCPharmer restrictions, seventeen compounds were found to have efficient binding to the heme group of CYP51B. Their effectiveness against CYP51B was tested using molecular docking, drug-likeness prediction, and molecular dynamics (MD) simulation. One compound (ZINC000015774018 or molecule-8) was found to inhibit the heme group with better drug-likeness than that found in the other sixteen drug-like compounds. MD simulations showed that this ligand introduced stabilized interactions with the targeted protein upon interacting with its heme and amino acid residues. Thus it may be used as a potent antifungal inhibitor against A. fumigatus.

scholarly journals Inactivation and reactivation of ribonuclease A studied by computer simulation

Open Biology ◽  
2012 ◽  
Vol 2 (7) ◽  
pp. 120088 ◽  
Author(s):  
Gavin M. Seddon ◽  
Robert P. Bywater
Keyword(s):  
Molecular Dynamics ◽  
Computer Simulation ◽  
In Silico ◽  
Tertiary Structure ◽  
Md Simulations ◽  
Globular Proteins ◽  
Ribonuclease A ◽  
Amino Acid Residues ◽  
Constituent Amino Acid ◽  
Single Protein

The year 2011 marked the half-centenary of the publication of what came to be known as the Anfinsen postulate, that the tertiary structure of a folded protein is prescribed fully by the sequence of its constituent amino acid residues. This postulate has become established as a credo , and, indeed, no contradictions seem to have been found to date. However, the experiments that led to this postulate were conducted on only a single protein, bovine ribonuclease A (RNAse). We conduct molecular dynamics (MD) simulations on this protein with the aim of mimicking this experiment as well as making the methodology available for use with basically any protein. There have been many attempts to model denaturation and refolding processes of globular proteins in silico using MD, but only a few examples where disulphide-bond containing proteins were studied. We took the view that if the reductive deactivation and oxidative reactivation processes of RNAse could be modelled in silico, this would provide valuable insights into the workings of the classical Anfinsen experiment.

scholarly journals Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA

2020 ◽  
Author(s):  
Bello Martiniano ◽  
Martínez-Muñoz Alberto ◽  
Balbuena-Rebolledo Irving
Keyword(s):  
Md Simulation ◽  
Potent Inhibitor ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Generalized Born ◽  
Main Protease ◽  
Promising Target ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

Abstract Among targets selected for studies aimed to identify potential inhibitors against COVID-19, SARS-CoV2 main proteinase (Mpro) is highlighted. Mpro is indispensable for virus replication, and is a promising target of potential inhibitors of COVID-19. Recently, monomeric SARS-CoV2 Mpro, drug repurposing and docking methods have facilitated the identification of several potential inhibitors. Results were refined through the assessment of dimeric SARS-CoV2 Mpro, which represents the functional state of enzyme. Docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area (MM/GBSA) studies indicated that dimeric Mpro most significantly impacts binding affinity tendency compared with the monomeric state, which suggesting that dimeric state is most useful when performing studies aimed to identify drugs targeting Mpro. In this study, we extend previous research by performing docking and MD simulation studies coupled with an MM/GBSA approach to assess binding of dimeric SARS-CoV2 Mpro to 12 FDA-approved drugs (darunavir, indinavir, saquinavir, tipranavir, diosmin, hesperidin, rutin, raltegravir, velpatasvir, ledipasvir, rosuvastatin and bortezomib), which were identified as the best candidates for treatment of COVID-19 in some previous dockings studies involving monomeric SARS-CoV2 Mpro. This analysis identified saquinavir as a potent inhibitor of dimeric SARS-CoV2 Mpro, therefore, the compound may have clinical utility against COVID-19.

scholarly journals Combinatorial Virtual Library Screening Study of Transforming Growth Factor-β2–Chondroitin Sulfate System

2021 ◽  
Vol 22 (14) ◽  
pp. 7542
Author(s):  
Nehru Viji Sankaranarayanan ◽  
Balaji Nagarajan ◽  
Umesh R. Desai
Keyword(s):  
Growth Factor ◽  
Chondroitin Sulfate ◽  
In Silico ◽  
Transforming Growth Factor ◽  
High Specificity ◽  
Md Simulations ◽  
Library Screening ◽  
Virtual Library ◽  
Gag Protein ◽  
High Affinity

Transforming growth factor-beta (TGF-β), a member of the TGF-β cytokine superfamily, is known to bind to sulfated glycosaminoglycans (GAGs), but the nature of this interaction remains unclear. In a recent study, we found that preterm human milk TGF-β2 is sequestered by chondroitin sulfate (CS) in its proteoglycan form. To understand the molecular basis of the TGF-β2–CS interaction, we utilized the computational combinatorial virtual library screening (CVLS) approach in tandem with molecular dynamics (MD) simulations. All possible CS oligosaccharides were generated in a combinatorial manner to give 24 di- (CS02), 192 tetra- (CS04), and 1536 hexa- (CS06) saccharides. This library of 1752 CS oligosaccharides was first screened against TGF-β2 using the dual filter CVLS algorithm in which the GOLDScore and root-mean-square-difference (RMSD) between the best bound poses were used as surrogate markers for in silico affinity and in silico specificity. CVLS predicted that both the chain length and level of sulfation are critical for the high affinity and high specificity recognition of TGF-β2. Interestingly, CVLS led to identification of two distinct sites of GAG binding on TGF-β2. CVLS also deduced the preferred composition of the high specificity hexasaccharides, which were further assessed in all-atom explicit solvent MD simulations. The MD results confirmed that both sites of binding form stable GAG–protein complexes. More specifically, the highly selective CS chains were found to engage the TGF-β2 monomer with high affinity. Overall, this work present key principles of recognition with regard to the TGF-β2–CS system. In the process, it led to the generation of the in silico library of all possible CS oligosaccharides, which can be used for advanced studies on other protein–CS systems. Finally, the study led to the identification of unique CS sequences that are predicted to selectively recognize TGF-β2 and may out-compete common natural CS biopolymers.

In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

2020 ◽  
Author(s):  
Sahar Qazi ◽  
Mustafa Alhaji Isa ◽  
Adam Mustapha ◽  
Khalid Raza ◽  
Ibrahim Alkali Allamin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
Anacardium Occidentale ◽  
Upper Respiratory Tract ◽  
Ligand Complex ◽  
In Silico Docking ◽  
Main Protease

<p>The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of <i>Zingiber offinale</i> and <i>Anacardium occidentale</i> using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of <i>Zingiber offinale </i>and the leaves of <i>Anacardium occidentale. </i>These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), <i>Pan</i>-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907). </p>

In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

2020 ◽  
Author(s):  
Sahar Qazi ◽  
Mustafa Alhaji Isa ◽  
Adam Mustapha ◽  
Khalid Raza ◽  
Ibrahim Alkali Allamin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
Anacardium Occidentale ◽  
Upper Respiratory Tract ◽  
Ligand Complex ◽  
In Silico Docking ◽  
Main Protease

<p>The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of <i>Zingiber offinale</i> and <i>Anacardium occidentale</i> using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of <i>Zingiber offinale </i>and the leaves of <i>Anacardium occidentale. </i>These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), <i>Pan</i>-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907). </p>

Appraisal of the role of In silico Methods in Pyrazole based drug design

2020 ◽  
Vol 20 ◽  
Author(s):  
Smriti Sharma ◽  
Vinayak Bhatia
Keyword(s):  
Drug Design ◽  
In Silico ◽  
Md Simulations ◽  
Quantitative Structure Activity Relationship ◽  
Field Analysis ◽  
Computational Techniques ◽  
Neuroprotective Drugs ◽  
Pharmacological Potential ◽  
Available Information ◽  
Anti Fungal

: Pyrazole and its derivatives are a pharmacologically significant active scaffold that have innumerable physiological and pharmacological activities. They can be very good targets for the discovery of novel anti-bacterial, anticancer, anti-inflammatory, anti-fungal, anti-tubercular, antiviral, antioxidant, antidepressant, anti-convulsant and neuroprotective drugs. This review focuses on the importance of in silico manipulations of pyrazole and its derivatives for medicinal chemistry. The authors have discussed currently available information on the use of computational techniques like molecular docking, structure-based virtual screening (SBVS), molecular dynamics (MD) simulations, quantitative structure activity relationship (QSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to drug design using pyrazole moieties. Pyrazole based drug design is mainly dependent on the integration of experimental and computational approaches. The authors feel that more studies need to be done to fully explore the pharmacological potential of the pyrazole moiety and in silico method can be of great help.

In Silico and in Vitro Evaluation of Deamidation Effects on the Stability of the Fusion Toxin DAB389IL-2

2019 ◽  
Vol 16 (4) ◽  
pp. 307-313 ◽  
Author(s):  
Nasrin Zarkar ◽  
Mohammad Ali Nasiri Khalili ◽  
Fathollah Ahmadpour ◽  
Sirus Khodadadi ◽  
Mehdi Zeinoddini
Keyword(s):  
In Silico ◽  
Catalytic Domain ◽  
Md Simulations ◽  
Special Importance ◽  
Native Form ◽  
Vitro Experiment ◽  
In Vitro Experiment ◽  
Pharmaceutical Protein ◽  
The Stability

Background: DAB389IL-2 (Denileukin diftitox) as an immunotoxin is a targeted pharmaceutical protein and is the first immunotoxin approved by FDA. It is used for the treatment of various kinds of cancer such as CTCL lymphoma, melanoma, and Leukemia but among all of these, treatment of CTCL has special importance. DAB389IL-2 consists of two distinct parts; the catalytic domain of Diphtheria Toxin (DT) that genetically fused to the whole IL-2. Deamidation is the most important reaction for chemical instability of proteins occurs during manufacture and storage. Deamidation of asparagine residues occurs at a higher rate than glutamine residues. The structure of proteins, temperature and pH are the most important factors that influence the rate of deamidation. Methods: Since there is not any information about deamidation of DAB389IL-2, we studied in silico deamidation by Molecular Dynamic (MD) simulations using GROMACS software. The 3D model of fusion protein DAB389IL-2 was used as a template for deamidation. Then, the stability of deamidated and native form of the drug was calculated. Results: The results of MD simulations were showed that the deamidated form of DAB389IL-2 is more unstable than the normal form. Also, deamidation was carried by incubating DAB389IL-2, 0.3 mg/ml in ammonium hydrogen carbonate for 24 h at 37o C in order to in vitro experiment. Conclusion: The results of in vitro experiment were confirmed outcomes of in silico study. In silico and in vitro experiments were demonstrated that DAB389IL-2 is unstable in deamidated form.

A comprehensive in silico study towards understanding the inhibitory mechanism of Lactoperoxidase by Dapsone and Propofol

2020 ◽  
Vol 16 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Kumar Jha ◽  
Gizachew Muluneh Amera ◽  
Jayaraman Muthukumaran ◽  
Rashmi Prabha Singh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Protoporphyrin Ix ◽  
Md Simulations ◽  
Prosthetic Group ◽  
Drug Molecules ◽  
Group A ◽  
Complex Forms ◽  
Covalently Linked

Introduction: Lactoperoxidase (LPO) is a member of mammalian heme peroxidase family and is an enzyme of innate immune system. It possesses a covalently linked heme prosthetic group (a derivative of protoporphyrin IX) in its active site. LPO catalyzes the oxidation of halides and pseudohalides in the presence of hydrogen peroxide (H2O2) and shows a broad range of antimicrobial activity. Methods: In this study, we have used two pharmaceutically important drug molecules, namely dapsone and propofol, which are earlier reported as potent inhibitors of LPO. Whereas the stereochemistry and mode of binding of dapsone and propofol to LPO is still not known because of the lack of the crystal structure of LPO with these two drugs. In order to fill this gap, we utilized molecular docking and molecular dynamics (MD) simulation studies of LPO in native and complex forms with dapsone and propofol. Results: From the docking results, the estimated binding free energy (ΔG) of -9.25 kcal/mol (Ki = 0.16 μM) and -7.05 kcal/mol (Ki = 6.79 μM) was observed for dapsone, and propofol, respectively. The standard error of Auto Dock program is 2.5 kcal/mol; therefore, molecular docking results alone were inconclusive. Conclusion: To further validate the docking results, we performed MD simulation on unbound, and two drugs bounded LPO structures. Interestingly, MD simulations results explained that the structural stability of LPO-Propofol complex was higher than LPO-Dapsone complex. The results obtained from this study establish the mode of binding and interaction pattern of the dapsone and propofol to LPO as inhibitors.

scholarly journals Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sensen Zhang ◽  
Baolei Yuan ◽  
Jordy Homing Lam ◽  
Jun Zhou ◽  
Xuan Zhou ◽  
...  
Keyword(s):  
Md Simulation ◽  
Potential Role ◽  
Md Simulations ◽  
Full Length ◽  
Inflammasome Activation ◽  
Simulation Studies ◽  
Cryo Electron Microscopy ◽  
Gating Mechanism ◽  
Atp Efflux

AbstractPannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.

scholarly journals Nitrogen, Iron and Zinc Acquisition: Key Nutrients to Aspergillus fumigatus Virulence

2021 ◽  
Vol 7 (7) ◽  
pp. 518
Author(s):  
Uxue Perez-Cuesta ◽  
Xabier Guruceaga ◽  
Saioa Cendon-Sanchez ◽  
Eduardo Pelegri-Martinez ◽  
Fernando L. Hernando ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Zinc Metabolism ◽  
Wide Field ◽  
Regulation Process ◽  
Number Of Genes ◽  
Iron And Zinc ◽  
Fungal Nutrition

Aspergillus fumigatus is a ubiquitous soil decomposer and an opportunistic pathogen that is characterized by its large metabolic machinery for acquiring nutrients from media. Lately, an ever-increasing number of genes involved in fungal nutrition has been associated with its virulence. Of these, nitrogen, iron, and zinc metabolism-related genes are particularly noteworthy, since 78% of them have a direct implication in virulence. In this review, we describe the sensing, uptake and regulation process of the acquisition of these nutrients, the connections between pathways and the virulence-implicated genes. Nevertheless, only 40% of the genes mentioned in this review have been assayed for roles in virulence, leaving a wide field of knowledge that remains uncertain and might offer new therapeutic and diagnostic targets.

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