scholarly journals Virtual Screening for Potential Inhibitors of Human Hexokinase II for the Development of Anti-Dengue Therapeutics

BioTech ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 1
Author(s):  
Suriyea Tanbin ◽  
Fazia Adyani Ahmad Fuad ◽  
Azzmer Azzar Abdul Hamid
Keyword(s):  
Hydrogen Bonds ◽  
Binding Energies ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Hexokinase Ii ◽  
Tropical Regions ◽  
Lipinski’S Rule ◽  
Viral Propagation ◽  
C Terminus ◽  
Similarity Scores

Dengue fever, which is a disease caused by the dengue virus (DENV), is a major unsolved issue in many tropical and sub-tropical regions of the world. The absence of treatment that effectively prevent further viral propagation inside the human’s body resulted in a high number of deaths globally each year. Thus, novel anti-dengue therapies are required for effective treatment. Human hexokinase II (HKII), which is the first enzyme in the glycolytic pathway, is an important drug target due to its significant impact on viral replication and survival in host cells. In this study, 23.1 million compounds were computationally-screened against HKII using the Ultrafast Shape Recognition with a CREDO Atom Types (USRCAT) algorithm. In total, 300 compounds with the highest similarity scores relative to three reference molecules, known as Alpha-D-glucose (GLC), Beta-D-glucose-6-phosphate (BG6), and 2-deoxyglucose (2DG), were aligned. Of these 300 compounds, 165 were chosen for further structure-based screening, based on their similarity scores, ADME analysis, the Lipinski’s Rule of Five, and virtual toxicity test results. The selected analogues were subsequently docked against each domain of the HKII structure (PDB ID: 2NZT) using AutoDock Vina programme. The three top-ranked compounds for each query were then selected from the docking results based on their binding energy, the number of hydrogen bonds formed, and the specific catalytic residues. The best docking results for each analogue were observed for the C-terminus of Chain B. The top-ranked analogues of GLC, compound 10, compound 26, and compound 58, showed predicted binding energies of −7.2, −7.0, and −6.10 kcal/mol and 7, 5, and 2 hydrogen bonds, respectively. The analogues of BG6, compound 30, compound 36, and compound 38, showed predicted binding energies of −7.8, −7.4, and −7.0 kcal/mol and 11, 9, and 5 hydrogen bonds, while the top three analogues of 2DG, known as compound 1, compound 4, and compound 31, showed predicted binding energies of −6.8, −6.3, and −6.3 kcal/mol and 4, 3, and 1 hydrogen bonds, sequentially. The highest-ranked compounds in the docking analysis were then selected for molecular dynamics simulation, where compound 10, compound 30, and compound 1, which are the analogues of GLC, BG6, and 2DG, have shown strong protein-ligand stability with an RMSD value of ±5.0 A° with a 5 H bond, ±4.0 A° with an 8 H bond, and ±0.5 A° with a 2 H bond, respectively, compared to the reference molecules throughout the 20 ns simulation time. Therefore, by using the computational studies, we proposed novel compounds, which may act as potential drugs against DENV by inhibiting HKII’s activity.

scholarly journals Natural xanthone compounds as promising drug candidates against COVID-19 - An integrated molecular docking and dynamics simulation study

2020 ◽  
Author(s):  
Shravan Kumar Gunda ◽  
Hima Kumari P ◽  
Gourav Choudhir ◽  
Anuj Kumar ◽  
P B. Kavi Kishor ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antiviral Agents ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Lipinski’S Rule ◽  
Drug Candidates ◽  
Main Protease ◽  
Lipinski’S Rule Of Five ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease2019 (COVID-19). SARS-CoV-2 is known for its high pathogenicity and transmission due to thepresence of polybasic cleavage sites. No specific drug is available for the treatment. To identifythe potential inhibitors, we have performed molecular docking against the SARS-CoV-2 mainprotease (6Y84) with fifteen important natural xanthone compounds. The docking results showedall the compounds exhibited good binding energies and interactions with the main protease. Thevalidation of representative docking complexes through molecular dynamics simulations showedthat xanthones binds with a higher binding affinity and lower free energy than the standardligand with Brasixanthone C and Brasixanthone B on 50 ns. Natural xanthone compounds havealso passed the Absorption, Distribution, Metabolism, and Excretion (ADME) property criteriaas well as Lipinski’s rule of five. The present integrated molecular docking and dynamicssimulations study unveil the use of xanthones as potential antiviral agents against SARS-CoV-2.

scholarly journals Natural xanthone compounds as promising drug candidates against COVID-19 - An integrated molecular docking and dynamics simulation study

2021 ◽  
Author(s):  
Shravan Kumar Gunda ◽  
Hima Kumari P ◽  
Anuj Kumar ◽  
P B. Kavi Kishor ◽  
Anil Kumar S
Keyword(s):  
Molecular Docking ◽  
Antiviral Agents ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Lipinski’S Rule ◽  
Drug Candidates ◽  
Main Protease ◽  
Lipinski’S Rule Of Five ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease2019 (COVID-19). SARS-CoV-2 is known for its high pathogenicity and transmission due to thepresence of polybasic cleavage sites. No specific drug is available for the treatment. To identifythe potential inhibitors, we have performed molecular docking against the SARS-CoV-2 mainprotease (6Y84) with fifteen important natural xanthone compounds. The docking results showedall the compounds exhibited good binding energies and interactions with the main protease. Thevalidation of representative docking complexes through molecular dynamics simulations showedthat xanthones binds with a higher binding affinity and lower free energy than the standardligand with Brasixanthone C and Brasixanthone B on 50 ns. Natural xanthone compounds havealso passed the Absorption, Distribution, Metabolism, and Excretion (ADME) property criteriaas well as Lipinski’s rule of five. The present integrated molecular docking and dynamicssimulations study unveil the use of xanthones as potential antiviral agents against SARS-CoV-2.

scholarly journals Resveratrol Inhibits Venezuelan Equine Encephalitis Virus Infection by Interfering with the AKT/GSK Pathway

Plants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 346
Author(s):  
Caitlin W. Lehman ◽  
Kylene Kehn-Hall ◽  
Megha Aggarwal ◽  
Nicole R. Bracci ◽  
Han-Chi Pan ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Fluorescent Protein ◽  
Glycogen Synthase ◽  
Venezuelan Equine Encephalitis Virus ◽  
Encephalitis Virus ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Luciferase Reporter ◽  
Venezuelan Equine Encephalitis ◽  
Equine Encephalitis Virus

The host proteins Protein Kinase B (AKT) and glycogen synthase kinase-3 (GSK-3) are associated with multiple neurodegenerative disorders. They are also important for the replication of Venezuelan equine encephalitis virus (VEEV), thereby making the AKT/GSK-3 pathway an attractive target for developing anti-VEEV therapeutics. Resveratrol, a natural phytochemical, has been shown to substantially inhibit the AKT pathway. Therefore, we attempted to explore whether it exerts any antiviral activity against VEEV. In this study, we utilized green fluorescent protein (GFP)- and luciferase-encoding recombinant VEEV to determine the cytotoxicity and antiviral efficacy via luciferase reporter assays, flow cytometry, and immunofluorescent assays. Our results indicate that resveratrol treatment is capable of inhibiting VEEV replication, resulting in increased viability of Vero and U87MG cells as well as reduced virion production and viral RNA contents within host cells for at least 48 h with a single treatment. Furthermore, the suppression of apoptotic signaling adaptors, caspase-3, caspase-7, and annexin V may also be implicated in resveratrol-mediated antiviral activity. We found that decreased phosphorylation of the AKT/GSK-3 pathway, mediated by resveratrol, can be triggered during the early stages of VEEV infection, suggesting that resveratrol disrupts the viral replication cycle and consequently promotes cell survival. Finally, molecular docking and dynamics simulation studies revealed that resveratrol can directly bind to VEEV glycoproteins, which may interfere with virus attachment and entry. In conclusion, our results suggest that resveratrol exerts inhibitory activity against VEEV infection and upon further modification could be a useful compound to study in neuroprotective research and veterinary sciences.

scholarly journals Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): an in silico analysis to identify novel drug candidates to combat COVID-19 pandemic

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Ghazala Muteeb ◽  
Adil Alshoaibi ◽  
Mohammad Aatif ◽  
Md. Tabish Rehman ◽  
M. Zuhaib Qayyum
Keyword(s):  
Hydrophobic Interactions ◽  
In Silico Analysis ◽  
Salt Bridge ◽  
Competitive Inhibitor ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Energy Calculation

AbstractThe recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score <  − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski’s, Veber’s, PAINS and Brenk’s filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies.

scholarly journals Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein–Peptide Docking and Molecular Dynamics Simulation

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 3018 ◽  
Author(s):  
Gao Tu ◽  
Tingting Fu ◽  
Fengyuan Yang ◽  
Lixia Yao ◽  
Weiwei Xue ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Electrostatic Interactions ◽  
Binding Free Energy ◽  
Computational Simulation ◽  
Critical Role ◽  
Dynamics Simulation ◽  
Peptide Docking ◽  
C Terminus ◽  
Free Energy Decomposition

The interaction of death-associated protein kinase 1 (DAPK1) with the 2B subunit (GluN2B) C-terminus of N-methyl-D-aspartate receptor (NMDAR) plays a critical role in the pathophysiology of depression and is considered a potential target for the structure-based discovery of new antidepressants. However, the 3D structures of C-terminus residues 1290–1310 of GluN2B (GluN2B-CT1290-1310) remain elusive and the interaction between GluN2B-CT1290-1310 and DAPK1 is unknown. In this study, the mechanism of interaction between DAPK1 and GluN2B-CT1290-1310 was predicted by computational simulation methods including protein–peptide docking and molecular dynamics (MD) simulation. Based on the equilibrated MD trajectory, the total binding free energy between GluN2B-CT1290-1310 and DAPK1 was computed by the mechanics generalized born surface area (MM/GBSA) approach. The simulation results showed that hydrophobic, van der Waals, and electrostatic interactions are responsible for the binding of GluN2B-CT1290–1310/DAPK1. Moreover, through per-residue free energy decomposition and in silico alanine scanning analysis, hotspot residues between GluN2B-CT1290-1310 and DAPK1 interface were identified. In conclusion, this work predicted the binding mode and quantitatively characterized the protein–peptide interface, which will aid in the discovery of novel drugs targeting the GluN2B-CT1290-1310 and DAPK1 interface.

scholarly journals Polypharmacology of Some Medicinal Plant Metabolites Against SARS-CoV-2 and Host Targets: Molecular Dynamics Evaluation of NSP9 RNA Binding Protein

2020 ◽  
Author(s):  
Suritra Bandyopadhyay ◽  
Omobolanle Abimbola Abiodun ◽  
Blessing Chinweotito Ogboo ◽  
Adeola Tawakalitu Kola-Mustapha ◽  
Emmanuel Ifeanyi Attah ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Medicinal Plants ◽  
Active Sites ◽  
Rna Binding ◽  
Hydrophobic Interactions ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Receptor Interaction ◽  
Plant Metabolites ◽  
Structure Comparison

<p><b>Background: </b>Medicinal plants, as rich sources of bioactive compounds with antiviral properties, are now being explored for the development of drugs against SARS-CoV-2.</p><p><b>Aims: </b>Identification of promising compounds for the treatment of COVID-19 from natural products via molecular modelling against NSP9, including some other viral and host targets and evaluation of polypharmacological indications.</p><p><b>Main methods: </b>A manually curated library of 521 phytochemicals (from 19 medicinal plants) was virtually screened using Mcule server and binding interactions were studied using DS Visualiser. Docking thresholds were set based on the scores of standard controls and rigorous ADMET properties were used to finally get the potential inhibitors. Free binding energies of the docked complexes were calculated employing MM-GBSA method. MM-GBSA informed our choice for MD simulation studies performed against NSP9 to study the stability of the drug-receptor interaction. NSP9 structure comparison was also performed. </p><p><b>Key findings: </b>Extensive screening of the molecules identified 5 leads for NSP9, 23 for Furin, 18 for ORF3a, and 19 for interleukin-6. Ochnaflavone and Licoflavone B, obtained from Lonicera japonica (Japanese Honeysuckle) and Glycyrrhiza glabra (Licorice), respectively, were identified to have the highest potential multi-target inhibition properties for NSP9, furin, ORF3a, and IL-6. Additionally, molecular dynamics simulation supports the robust stability of Ochnaflavone and Licoflavone B against NSP9 at the active sites via hydrophobic interactions, H-bonding, and H-bonding facilitated by water.</p><b>Significance:</b> These compounds with the highest drug-like ranking against multiple viral and host targets have the potential to be drug candidates for the treatment of SARS-CoV-2 infection that may possibly act on multiple pathways simultaneously to inhibit viral entry and replication as well as disease progression.

scholarly journals Chemical Energetics and Atomic Charges Distribution of Variably Sized Hydrated Sulfate Clusters in the light of Density Functional Theory

2021 ◽  
Vol 25 (1) ◽  
pp. 595
Author(s):  
Anant Babu Marahatta
Keyword(s):  
Structural Stability ◽  
Density Functional ◽  
Hydration Number ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Water Molecules ◽  
Atomic Charges ◽  
Electronic Interactions ◽  
Hydrogen Bond Formation ◽  
Depth Analysis

Among the ions classified in the Hofmeister series, the firstly ranked divalent sulfate anion has the strongest hydrating and water-structure making propensity. This unique characteristic actually makes it kosmotropic which causes water molecules to interact each other and contributes to gain structural stability of its hydrated clusters [SO42−(H2O)n]n = 1−40. In this study, few variably sized microhydrated sulfate clusters [SO42−(H2O)n]n = 1−4, 16 are considered separately, and inquired their chemical energetics and atomic charge distributions through ab initio based theoretical model. The main objective of this insight is to specify and interpret their thermodynamic stabilities, binding energies, and specific bonding and electronic interactions quantum mechanically. An in-depth analysis of their change in relative ground state electronic energy with respect to hydration number indicates stronger affinity of the sulfate ion towards water molecules while attaining structural stability in any aqueous type solutions. The mathematically determined values of their binding energy (DE) almost holds up the same with this structural stability order: [SO42−(H2O)16] > [SO42−(H2O)4] > [SO42−(H2O)3] > [SO42−(H2O)2] > [SO42−(H2O)], as reliable as experimentally and molecular dynamics simulation predicted trend. Moreover, the Mulliken derived partial atomic charges feature qualitative charge distribution in them which not only depicts electronic interactions between the specific atoms but also exemplifies the involvement of central sulfate units in hydrogen bond formation with surrounding water molecules.

Computational Discovery of SARS-CoV-2 NSP 16 Drug Candidates Based on Pharmacophore Modeling and Molecular Dynamics Simulation

2021 ◽  
Vol 20 (04) ◽  
pp. 377-390
Author(s):  
Zahra Hesari ◽  
Samaneh Zolghadri ◽  
Sajad Moradi ◽  
Mohsen Shahlaei ◽  
Elham Tazikeh-Lemeski
Keyword(s):  
Molecular Dynamics ◽  
Study Drug ◽  
Pharmacophore Modeling ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Structural Protein ◽  
Drug Candidates ◽  
Computational Discovery ◽  
Approved Drugs ◽  
Dynamics Simulations

Non-Structural Protein 16 (NSP-16) is one of the most suitable targets for discovery of drugs for corona viruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been accomplished by pharmacophore-based virtual screening among some analogs (FDA approved drugs) and marine natural plants (MNP). The comparison of the binding energies and the inhibition constants was determined using molecular docking method. Three compounds including two FDA approved (Ibrutinib, Idelalisib) and one MNP (Kumusine) were selected for further investigation using the molecular dynamics simulations. The results indicated that Ibrutinib and Idelalisib are oral medications while Kumusine, with proper hydrophilic and solubility properties, is an appropriate candidate for nsp-16 inhibitor and can be effective to control COVID-19 disease.

scholarly journals The Importance of CH···X (X = O, π) Interaction of a New Mixed Ligand Cu(II) Coordination Polymer: Structure, Hirshfeld Surface and Theoretical Studies

Crystals ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. 455 ◽  
Author(s):  
Saikat Seth
Keyword(s):  
Solid State ◽  
Hydrogen Bonds ◽  
Noncovalent Interactions ◽  
Carbonyl Oxygen ◽  
Hirshfeld Surface ◽  
Mixed Ligand ◽  
Binding Energies ◽  
Zigzag Chain ◽  
X Ray ◽  
Π Interactions

In this study, a new equimolar (1:1:1) mixed ligand Cu(II) polymer, [Cu(IDA)(ImP)]n (1) with iminodiacetato (IDA) and imidazo[1,2-a]-pyridine (ImP) was synthesized and characterized by single crystal X-ray diffraction analysis. X-ray crystallography reveals that compound (1) consists of polymeric zigzag chain along [010] the carboxylate carbonyl oxygen atom by two-fold symmetry screw axis. The solid-state structure is stabilized through C–H···O hydrogen bonds and C–H···π interactions that lead the molecules to generate two-dimensional supramolecular assemblies. The intricate combinations of hydrogen bonds and C–H···π interactions are fully described along with computational studies. A thorough analysis of Hirshfeld surface and fingerprint plots elegantly quantify the interactions involved within the structure. The binding energies associated with the noncovalent interactions observed in the crystal structure and the interplay between them were calculated using theoretical DFT calculations. Weak noncovalent interactions were analyzed and characterized using Bader’s theory of ‘‘atoms-in-molecules’’ (AIM). Finally, the solid-state supramolecular assembly was characterized by the “Noncovalent Interaction” (NCI) plot index.

The achiral tetrapeptideZ-Aib-Aib-Aib-Gly-OtBu

2014 ◽  
Vol 70 (11) ◽  
pp. 1046-1049 ◽  
Author(s):  
Renate Gessmann ◽  
Hans Brückner ◽  
Kyriacos Petratos
Keyword(s):  
Hydrogen Bonds ◽  
Butyl Ester ◽  
Relative Orientation ◽  
Asymmetric Unit ◽  
Intramolecular Hydrogen Bonds ◽  
Aminoisobutyric Acid ◽  
C Terminus ◽  
Intramolecular Hydrogen

The title achiral peptideN-benzyloxycarbonyl-α-aminoisobutyryl-α-aminoisobutyryl-α-aminoisobutyrylglycinetert-butyl ester orZ-Aib-Aib-Aib-Gly-OtBu (Aib is α-aminoisobutyric acid,Zis benzyloxycarbonyl, Gly is glycine and OtBu indicates thetert-butyl ester), C26H40N4O7, is partly hydrated (0.075H2O) and has two different conformations which together constitute the asymmetric unit. Both molecules form incipient 310-helices. They differ in the relative orientation of the N-terminal protection group and at the C-terminus. There are two 4→1 intramolecular hydrogen bonds.

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