Phytomedicine in Disease Management: In-Silico Analysis of the Binding Affinity of Artesunate and Azadirachtin for Malaria Treatment

In the rural communities of sub-Saharan African (sSA) countries, malaria is being managed using phytocompounds. Artesunate is reported to inhibit Gephyrin E, a central, multi-domain scaffolding protein of inhibitory post-synapses. Neem plant and its metabolites like azadirachtin are being indicated for management of malaria by traditional healers. The present study was aimed to cheminformatically analyse the binding potential of artesunate and azadirachtin with various reactive moieties of Gephyrin E, to reduce malaria scourge. With molecular dynamics (MD), binding free energy estimation and binding affinity of artesunate and azadirachtin to Gephyrin E was done. GRIP docking was done to study the interactions of these test ligands with Gephyrin E (6FGC). MD simulation gave insights to structural changes upon binding of artesunate and azadirachtin in the ligand-binding pocket of Gephyrin E. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) were calculated. From the estimation, azadirachtin had a total binding energy of −36.97 kcal/mol; artesunate had a binding energy of −35.73 kcal/mol. The GRIP docking results provided a clearer evidence that artesunate has comparatively better binding affinity to Gephyrin E than azadirachtin, and the critical binding sites (in activity order) were cavity 3, 2, 8, and 6 for artesunate while for azadirachtin, it was cavity 6, 3, 8, and 2. The GRIP docking provided detailed interactions at the atomic levels, providing evidence; both compounds have chances to overcome the drug resistance problem, albeit higher for artesunate. Our findings added another piece of evidence that azadirachtin may be effective as an anti-malarial agent. The results herein may provide impetus for more studies into bioactive components of plant origin towards the effective management of malaria disease phenotype.

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Luteolin and abyssinone II as potential inhibitors of SARS-CoV-2: an in silico molecular modeling approach in battling the COVID-19 outbreak

Bulletin of the National Research Centre ◽

10.1186/s42269-020-00479-6 ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

Mohammad Mahfuz Ali Khan Shawan ◽

Sajal Kumar Halder ◽

Md. Ashraful Hasan

Keyword(s):

Molecular Dynamics ◽

Root Mean Square ◽

In Silico ◽

Binding Free Energy ◽

Biologically Active ◽

Dynamics Simulation ◽

Mean Square ◽

Efficient Treatment ◽

Target Proteins

Abstract Background At present, the entire world is in a war against COVID-19 pandemic which has gradually led us toward a more compromised “new normal” life. SARS-CoV-2, the pathogenic microorganism liable for the recent COVID-19 outbreak, is extremely contagious in nature resulting in an unusual number of infections and death globally. The lack of clinically proven therapeutic intervention for COVID-19 has dragged the world’s healthcare system into the biggest challenge. Therefore, development of an efficient treatment scheme is now in great demand. Screening of different biologically active plant-based natural compounds could be a useful strategy for combating this pandemic. In the present research, a collection of 43 flavonoids of 7 different classes with previously recorded antiviral activity was evaluated via computational and bioinformatics tools for their impeding capacity against SARS-CoV-2. In silico drug likeness, pharmacophore and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile analysis of the finest ligands were carried out using DataWarrior, DruLiTo and admetSAR programs, respectively. Molecular docking was executed by AutoDock Vina, while molecular dynamics simulation of the target protein–ligand bound complexes was done using nanoscalable molecular dynamics and visual molecular dynamics software package. Finally, the molecular target analysis of the selected ligands within Homo sapiens was conducted with SwissTargetPredcition web server. Results Out of the forty-three flavonoids, luteolin and abyssinone II were found to develop successful docked complex within the binding sites of target proteins in terms of lowest binding free energy and inhibition constant. The root mean square deviation and root mean square fluctuation values of the docked complex displayed stable interaction and efficient binding between the ligands and target proteins. Both of the flavonoids were found to be safe for human use and possessed good drug likeness properties and target accuracy. Conclusions Conclusively, the current study proposes that luteolin and abyssinone II might act as potential therapeutic candidates for SARS-CoV-2 infection. In vivo and in vitro experiments, however, should be taken under consideration to determine the efficiency and to demonstrate the mechanism of action.

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SHELL MODEL CALCULATIONS OF 3T, 5He AND 6Li NUCLEI

International Journal of Modern Physics E ◽

10.1142/s0218301302000685 ◽

2002 ◽

Vol 11 (01) ◽

pp. 67-70

Author(s):

NAZIH EL-NOHY

Keyword(s):

Binding Energy ◽

Shell Model ◽

Root Mean Square ◽

Long Range ◽

Ground State ◽

Radial Dependence ◽

Spin Orbit ◽

Mean Square ◽

Model Calculations ◽

Short Range Repulsion

The bases of the translation invariant shell model are used to construct the ground-state wave functions of 3 T , 5 He and 6 Li . For 3 T the bases used correspond to the number of quanta of excitation N up to ten. For 5 He and 6 Li the bases used correspond to the number of quanta of excitation N up to six. The model is applied to calculate the binding energy and the root mean square radius for 3 T , 5 He and 6 Li nuclei. The residual interactions used consist of central, tensor, spin-orbit and quadratic spin-orbit terms with Gaussian radial dependence. The parameters of these interactions are chosen in such away that they represent the long range attraction and the short range repulsion of nucleon interactions. It was found that this potential is more suitable for calculating the characteristics of these nuclei, and better than other potentials, such as our previous potentials which were represented by the parameters of long range attraction forces only. For 3T we obtained good agreement between calculated and experimental values of both the ground state binding energy and the root mean square radius. For 5 He and 6 Li nuclei we obtained an acceptable improvement with these calculations over other potentials.

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The Effect of Deuteration on the H2 Receptor Histamine Binding Profile: A Computational Insight into Modified Hydrogen Bonding Interactions

Molecules ◽

10.3390/molecules25246017 ◽

2020 ◽

Vol 25 (24) ◽

pp. 6017

Author(s):

Lucija Hok ◽

Janez Mavri ◽

Robert Vianello

Keyword(s):

Hydrogen Bonding ◽

Binding Energy ◽

Binding Free Energy ◽

Receptor Activation ◽

Dynamics Simulation ◽

Computational Techniques ◽

Aqueous Environment ◽

Total Binding Energy ◽

H2 Receptor ◽

Hydrogen Bonding Interactions

We used a range of computational techniques to reveal an increased histamine affinity for its H2 receptor upon deuteration, which was interpreted through altered hydrogen bonding interactions within the receptor and the aqueous environment preceding the binding. Molecular docking identified the area between third and fifth transmembrane α-helices as the likely binding pocket for several histamine poses, with the most favorable binding energy of −7.4 kcal mol−1 closely matching the experimental value of −5.9 kcal mol−1. The subsequent molecular dynamics simulation and MM-GBSA analysis recognized Asp98 as the most dominant residue, accounting for 40% of the total binding energy, established through a persistent hydrogen bonding with the histamine −NH3+ group, the latter further held in place through the N–H∙∙∙O hydrogen bonding with Tyr250. Unlike earlier literature proposals, the important role of Thr190 is not evident in hydrogen bonds through its −OH group, but rather in the C–H∙∙∙π contacts with the imidazole ring, while its former moiety is constantly engaged in the hydrogen bonding with Asp186. Lastly, quantum-chemical calculations within the receptor cluster model and utilizing the empirical quantization of the ionizable X–H bonds (X = N, O, S), supported the deuteration-induced affinity increase, with the calculated difference in the binding free energy of −0.85 kcal mol−1, being in excellent agreement with an experimental value of −0.75 kcal mol−1, thus confirming the relevance of hydrogen bonding for the H2 receptor activation.

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Self-Organization Characteristics of Lunar Regolith Inferred by Yutu-2 Lunar Penetrating Radar

Remote Sensing ◽

10.3390/rs13153017 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3017

Author(s):

Xiang Zhang ◽

Wenmin Lv ◽

Lei Zhang ◽

Jinhai Zhang ◽

Yangting Lin ◽

...

Keyword(s):

Root Mean Square ◽

Structural Changes ◽

Structural Characteristics ◽

Lunar Regolith ◽

Homogeneous Medium ◽

Self Organization ◽

Mean Square ◽

Organization Model ◽

Correlation Distance ◽

Regolith Layer

Most previous studies tend to simplify the lunar regolith as a homogeneous medium. However, the lunar regolith is not completely homogeneous, because there are weak reflections from the lunar regolith layer. In this study, we examined the weak heterogeneity of the lunar regolith layer using a self-organization model by matching the reflection pattern of both the lunar regolith layer and the top of the ejecta layer. After a series of numerical experiments, synthetic results show great consistency with the observed Chang’E-4 lunar penetrating radar data and provide some constraints on the range of controlling parameters of the exponential self-organization model. The root mean square permittivity perturbation is estimated to be about 3% and the correlation distance is about 5–10 cm. Additionally, the upper layer of ejecta has about 1–2 rocks per square meter, and the rock diameter is about 20–30 cm. These parameters are helpful for further study of structural characteristics and the evolution process of the lunar regolith. The relatively small correlation distance and root mean square perturbation in the regolith indicate that the regolith is mature. The weak reflections within the regolith are more likely to be due to structural changes rather than material composition changes.

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Investigating Fungi-Derived Bioactive Molecules as Inhibitor of the SARS Coronavirus Papain Like Protease: Computational Based Study

Frontiers in Medicine ◽

10.3389/fmed.2021.752095 ◽

2021 ◽

Vol 8 ◽

Author(s):

Aweke Mulu Belachew ◽

Asheber Feyisa ◽

Seid Belay Mohamed ◽

Jerusalem Fekadu W/Mariam

Keyword(s):

Binding Affinity ◽

Root Mean Square ◽

Bioactive Compounds ◽

Bioactive Molecules ◽

World Health ◽

Solvent Accessible Surface Area ◽

Mean Square ◽

Sars Coronavirus ◽

Reference Drug ◽

Wet Lab

Due to the rapid growth of the COVID-19 pandemic and its outcomes, developing a remedy to fight the predicament is critical. So far, it has infected more than 214,468,601 million people and caused the death of 4,470,969 million people according to the August 27, 2021, World Health Organization's (WHO) report. Several studies have been published on both computational and wet-lab approaches to develop antivirals for COVID-19, although there has been no success yet. However, the wet-lab approach is laborious, expensive, and time-consuming, and computational techniques have screened the activity of bioactive compounds from different sources with less effort and cost. For this investigation, we screened the binding affinity of fungi-derived bioactive molecules toward the SARS coronavirus papain-like protease (PLpro) by using computational approaches. Studies showed that protease inhibitors can be very effective in controlling virus-induced infections. Additionally, fungi represent a vast source of bioactive molecules, which could be potentially used for antiviral therapy. Fifty fungi-derived bioactive compounds were investigated concerning SARS-CoV-2 PLpro by using Auto Dock 4.2.1, Gromacs 2018. 2, ADMET, Swiss-ADME, FAF-Drugs 4.023, pKCSM, and UCLA-DOE server. From the list of the screened bioactive compounds, Dihydroaltersolanol C, Anthraquinone, Nigbeauvin A, and Catechin were selected with the Auto-Dock results of −8.68, −7.52, −10.46, and −10.58 Kcal/mol, respectively, based on their binding affinity compared to the reference drug. We presented the drug likeliness, toxicity, carcinogenicity, and mutagenicity of all compounds using ADMET analysis. They interacted with the amino acid residues, Gly163, Trp106, Ser111, Asp164, and Cys270, through hydrogen bonds. The root-mean-square deviation (RMSD), root-mean-square fluctuations (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg) values revealed a stable interaction. From the overall analyses, we can conclude that Dihydroaltersolanol C, Anthraquinone, Nigbeauvin A, and Catechin are classified as promising candidates for PLpro, thus potentially useful in developing a medicine for COVID-19.

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Unraveling the Deleterious Effects of Cancer-Driven STK11 Mutants through Conformational Sampling Approach

Cancer Informatics ◽

10.4137/cin.s38044 ◽

2016 ◽

Vol 15 ◽

pp. CIN.S38044 ◽

Cited By ~ 2

Author(s):

Merlin Lopus ◽

D. Meshach Paul ◽

R. Rajasekaran

Keyword(s):

Binding Energy ◽

Root Mean Square ◽

Critical Role ◽

Intramolecular Interactions ◽

Solvent Accessible Surface Area ◽

Driver Mutations ◽

Radius Of Gyration ◽

Conformational Sampling ◽

Mean Square ◽

Structural Variations

Tumor suppressor gene, STK11, encodes for serine-threonine kinase, which has a critical role in regulating cell growth and apoptosis. Mutations of the same lead to the inactivation of STK11, which eventually causes different types of cancer. In this study, we focused on identifying those driver mutations through analyzing structural variations of mutants, viz., D194N, E199K, L160P, and Y49D. Native and the mutants were analyzed to determine their geometrical deviations such as root-mean-square deviation, root-mean-square fluctuation, radius of gyration, potential energy, and solvent-accessible surface area using conformational sampling technique. Additionally, the global minimized structure of native and mutants was further analyzed to compute their intramolecular interactions and distribution of secondary structure. Subsequently, simulated thermal denaturation and docking studies were performed to determine their structural variations, which in turn alter the formation of active complex that comprises STK11, STRAD, and MO25. The deleterious effect of the mutants would result in a comparative loss of enzyme function due to variations in their binding energy pertaining to spatial conformation and flexibility. Hence, the structural variations in binding energy exhibited by the mutants, viz., D194N, E199K, L160P, and Y49D, to that of the native, consequently lead to pathogenesis.

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THE STUDY OF DIBARYON SYSTEMS WITH STRANGENESS ON CHIRAL QUARK MODEL

Modern Physics Letters A ◽

10.1142/s021773230501532x ◽

2005 ◽

Vol 20 (01) ◽

pp. 69-77

Author(s):

HOURONG PANG ◽

JIALUN PING ◽

XIAOHUA WU

Keyword(s):

Binding Energy ◽

Quark Model ◽

Root Mean Square ◽

Bound State ◽

Group Method ◽

Chiral Quark Model ◽

Mean Square ◽

Narrow Resonance ◽

The Masses

We expand Salamanca SU (2) chiral quark model to SU (3) one and calculate promising dibaryon candidates with strangeness S=-3,-6 in the framework of resonating group method. We find that, besides ΩΩ, the mass of NΩ state is about 23–38 MeV lower than its threshold, it might appear as a bound state or a narrow resonance. The effect of K and η exchanges on the masses of strangeness and nonstrangeness systems has been studied and found to be negligible for nonstrangeness systems. However this effect brings some changes (about tens of MeV) on the masses of strangeness systems. We have also studied the sensitivities of binding energy and root mean square radius to the mass of s-quark.

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Insights from molecular docking and molecular dynamics on the potential of vitexin as an antagonist candidate against lipopolysaccharide (LPS) for microglial activation in neuroinflammation

BMC Biotechnology ◽

10.1186/s12896-021-00697-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

M. A. F. Yahaya ◽

A. R. Abu Bakar ◽

J. Stanslas ◽

N. Nordin ◽

M. Zainol ◽

...

Keyword(s):

Binding Energy ◽

Binding Site ◽

Root Mean Square ◽

Inflammatory Cytokines ◽

Nuclear Factor Κb ◽

Stable Complex ◽

Radius Of Gyration ◽

Mean Square ◽

Dynamic Simulations ◽

Pro Inflammatory Cytokines

Abstract Background Neuroinflammation has been identified to be the key player in most neurodegenerative diseases. If neuroinflammation is left to be unresolved, chronic neuroinflammation will be establish. Such situation is due to the overly-activated microglia which have the tendency to secrete an abundance amount of pro-inflammatory cytokines into the neuron microenvironment. The abundance of pro-inflammatory cytokines will later cause toxic and death to neurons. Toll-like receptor 4 (TLR4)/MD-2 complex found on the cell surface of microglia is responsible for the attachment of LPS and activation of nuclear factor-κB (NF-κB) downstream signalling pathway. Albeit vitexin has been shown to possess anti-inflammatory property, however, little is known on its ability to bind at the binding site of TLR4/MD-2 complex of microglia as well as to be an antagonist for LPS. Results The present study reveals that both vitexin and donepezil are able to bind at the close proximity of LPS binding site located at the TLR4/MD-2 complex with the binding energy of − 4.35 and − 9.14 kcal/mol, respectively. During molecular dynamic simulations, both vitexin and donepezil formed stable complex with TLR4/MD-2 throughout the 100 ns time length with the root mean square deviation (RMSD) values of 2.5 Å and 4.0 Å, respectively. The root mean square fluctuation (RMSF) reveals that both compounds are stable. Interestingly, the radius of gyration (rGyr) for donepezil shows notable fluctuations when compare with vitexin. The MM-GBSA results showed that vitexin has higher binding energy in comparison with donepezil. Conclusions Taken together, the findings suggest that vitexin is able to bind at the binding site of TLR4/MD-2 complex with more stability than donepezil throughout the course of 100 ns simulation. Hence, vitexin has the potential to be an antagonist candidate for LPS.

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Efficacy of Phytochemicals Derived from Avicennia officinalis for the Management of COVID-19: A Combined In Silico and Biochemical Study

Molecules ◽

10.3390/molecules26082210 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2210

Author(s):

Shafi Mahmud ◽

Gobindo Kumar Paul ◽

Mirola Afroze ◽

Shirmin Islam ◽

Swagota Briti Ray Gupt ◽

...

Keyword(s):

Root Mean Square ◽

Antioxidant Activities ◽

Binding Free Energy ◽

Healthcare Management ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Mean Square ◽

Main Protease ◽

Avicennia Officinalis

The recent coronavirus disease 2019 (COVID-19) pandemic is a global threat for healthcare management and the economic system, and effective treatments against the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for this disease have not yet progressed beyond the developmental phases. As drug refinement and vaccine progression require enormously broad investments of time, alternative strategies are urgently needed. In this study, we examined phytochemicals extracted from Avicennia officinalis and evaluated their potential effects against the main protease of SARS-CoV-2. The antioxidant activities of A. officinalis leaf and fruit extracts at 150 µg/mL were 95.97% and 92.48%, respectively. Furthermore, both extracts displayed low cytotoxicity levels against Artemia salina. The gas chromatography–mass spectroscopy analysis confirmed the identifies of 75 phytochemicals from both extracts, and four potent compounds, triacontane, hexacosane, methyl linoleate, and methyl palminoleate, had binding free energy values of −6.75, −6.7, −6.3, and −6.3 Kcal/mol, respectively, in complexes with the SARS-CoV-2 main protease. The active residues Cys145, Met165, Glu166, Gln189, and Arg188 in the main protease formed non-bonded interactions with the screened compounds. The root-mean-square difference (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond data from a molecular dynamics simulation study confirmed the docked complexes′ binding rigidity in the atomistic simulated environment. However, this study′s findings require in vitro and in vivo validation to ensure the possible inhibitory effects and pharmacological efficacy of the identified compounds.

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Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study

Molecules ◽

10.3390/molecules26175304 ◽

2021 ◽

Vol 26 (17) ◽

pp. 5304

Author(s):

Mohammad G. Al-Thiabat ◽

Amirah Mohd Gazzali ◽

Noratiqah Mohtar ◽

Vikneswaran Murugaiyah ◽

Ezatul Ezleen Kamarulzaman ◽

...

Keyword(s):

Molecular Dynamics ◽

Folic Acid ◽

Root Mean Square ◽

Active Site ◽

Md Simulation ◽

Binding Free Energy ◽

Cancer Drug ◽

Radius Of Gyration ◽

Mean Square ◽

The Stability

Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. In this study, FA was conjugated to beta-cyclodextrin (βCD) and subjected to in silico analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability for the conjugated system compared to unconjugated and apo systems (ligand free). Docking studies revealed that the conjugated FA bound into the active site of FRα with a docking score (free binding energy < −15 kcal/mol), with a similar binding pose to that of unconjugated FA. Subsequent analyses from molecular dynamics (MD) simulations, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) demonstrated that FA and FA–βCDs created more dynamically stable systems with FRα than the apo-FRα system. All systems reached equilibrium with stable RMSD values ranging from 1.9–2.4 Å and the average residual fluctuation values of the FRα backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 Å with a consistent Rg value of around 16.8 Å throughout the MD simulation time (0–100 ns). The conjugation with βCD improved the stability and decreased the mobility of all the residues (except residues 149–151) compared to FA–FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA), and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems.

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