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

2016 ◽  
Vol 15 ◽  
pp. CIN.S38044 ◽  
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.

scholarly journals Screening of Potent Phytochemical Inhibitors Against SARS-CoV-2 Main Protease: An Integrative Computational Approach

2021 ◽  
Vol 1 ◽  
Author(s):  
Shafi Mahmud ◽  
Md. Robiul Hasan ◽  
Suvro Biswas ◽  
Gobindo Kumar Paul ◽  
Shamima Afrose ◽  
...  
Keyword(s):  
Root Mean Square ◽  
Global Economy ◽  
Transmission Rate ◽  
Accessible Surface Area ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Protease Inhibition ◽  
Main Protease

Coronavirus disease 2019 (COVID-19) is a potentially lethal and devastating disease that has quickly become a public health threat worldwide. Due to its high transmission rate, many countries were forced to implement lockdown protocols, wreaking havoc on the global economy and the medical crisis. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus for COVID-19, represent an effective target for the development of a new drug/vaccine because it is well-conserved and plays a vital role in viral replication. Mpro inhibition can stop the replication, transcription as well as recombination of SARS-CoV-2 after the infection and thus can halt the formation of virus particles, making Mpro a viable therapeutic target. Here, we constructed a phytochemical dataset based on a rigorous literature review and explored the probability that various phytochemicals will bind with the main protease using a molecular docking approach. The top three hit compounds, medicagol, faradiol, and flavanthrin, had binding scores of −8.3, −8.6, and −8.8 kcal/mol, respectively, in the docking analysis. These three compounds bind to the active groove, consisting of His41, Cys45, Met165, Met49, Gln189, Thr24, and Thr190, resulting in main protease inhibition. Moreover, the multiple descriptors from the molecular dynamics simulation, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, radius of gyration, and hydrogen bond analysis, confirmed the stable nature of the docked complexes. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis confirmed a lack of toxicity or carcinogenicity for the screened compounds. Our computational analysis may contribute toward the design of an effective drug against the main protease of SARS-CoV-2.

scholarly journals Reappraisal of Trifluperidol against NSP-3 protein: Potential therapeutic for COVID-19

2020 ◽  
Author(s):  
Ajita Pandey
Keyword(s):  
Root Mean Square ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Scoring Functions ◽  
Mean Square ◽  
Structural Protein ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Novel coronavirus disease 2019 (COVID-19) is a highly infectious disease that is caused by the recently discovered severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Because there are no specific vaccines or drugs for SARS-CoV-2, drug repurposing may be a promising approach. SARS-CoV-2 has a positive-sense RNA genome that encodes non-structural proteins (Nsps), which are essential for viral replication in the host cell. Non-structural protein 3 (Nsp3) is a multidomain protein and is the largest protein of the replicase complex. Nsp3 contains an ADP-ribose phosphatase (ADRP) domain, also called the macrodomain, which interferes with the host immune response. In the present study, we used computational regression methods to target the ADRP domain of Nsp3, using FDA-approved drugs. We virtually screened 2,892 FDA-approved drugs, using a combination of molecular docking and scoring functions. Saquinavir and trifluperidol were identified as potential leads and were further investigated using molecular dynamics simulation (MDS) to predict the stability and behavior of the ADRP-drug complexes. Analysis of root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessible surface area and number of hydrogen bonds showed that the ADRP-trifluperidol complex is more stable than the ADRP-saquinavir complex. The screening and the MDS results suggest that trifluperidol is a novel inhibitor of the ADRP domain of Nsp3. Trifluperidol could, therefore, potentially be used to help control the spread of COVID-19, either alone or in combination with antiviral agents. Further in-vitro and in-vivo experiments are necessary to confirm our in silico results.

MOLECULAR DOCKING AND MOLECULAR DYNAMICS STUDIES OF THE INTERACTION BETWEEN COUMARIN-NEUROTRANSMITTER DERIVATIVES AND CARBONIC ANHYDRASE IX

2021 ◽  
Author(s):  
Dušan Dimić ◽  
◽  
Dejan Milenković ◽  
Edina Avdović ◽  
Goran Kaluđerović ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Carbonic Anhydrase ◽  
Root Mean Square ◽  
Binding Energies ◽  
Intramolecular Interactions ◽  
Biologically Active ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Native Ligand

Novel biologically active compounds can be obtained by the structural modification of coumarins. In this contribution, five new derivatives of 4-hydroxycoumarin with tyramine, octopamine, norepinephrine, 3-methoxytyramine, and dopamine were obtained. Their structures were optimized based on the previously obtained crystal structure of the 4-hydroxycoumarin-dopamine derivative. The special emphasis was put on the effect of various substituents on the structure of obtained compounds and intramolecular interactions governing the stability. To investigate their possible antitumor activity, molecular docking and molecular dynamics simulations were performed with Carbonic anhydrase, a prognostic factor in several cancers, and compared to the native ligand, 5-acetamido-1,3,4-thiadiazole- 2-sulfonamide. The results have shown that all of the coumarin-neurotransmitter derivatives bind to the active pocket of protein with the binding energies higher than for the native ligand. The main contributions to the binding energies were discussed. The Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and Radius of gyration (Rg), as results of MD simulations, were used to predict the activity of compounds towards chosen protein. The highest MD binding energies were obtained for the derivatives with dopamine and 3-methoxytyramine, with the van der Waals interaction and hydrogen bonds being the most important contributors.

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

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.

scholarly journals Plant-Based Phytochemical Screening by Targeting Main Protease of SARS-CoV-2 to Design Effective Potent Inhibitors

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 589
Author(s):  
Shafi Mahmud ◽  
Suvro Biswas ◽  
Gobindo Kumar Paul ◽  
Mohasana Akter Mita ◽  
Maria Meha Promi ◽  
...  
Keyword(s):  
Root Mean Square ◽  
Active Sites ◽  
Treatment Options ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Drug Candidates ◽  
Main Protease ◽  
Antibacterial And Antifungal

Currently, a worldwide pandemic has been declared in response to the spread of coronavirus disease 2019 (COVID-19), a fatal and fast-spreading viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The low availability of efficient vaccines and treatment options has resulted in a high mortality rate, bringing the world economy to its knees. Thus, mechanistic investigations of drugs capable of counteracting this disease are in high demand. The main protease (Mpro) expressed by SARS-CoV-2 has been targeted for the development of potential drug candidates due to the crucial role played by Mpro in viral replication and transcription. We generated a phytochemical library containing 1672 phytochemicals derived from 56 plants, which have been reported as having antiviral, antibacterial, and antifungal activity. A molecular docking program was used to screen the top three candidate compounds: epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate, which had respective binding affinities of −8.4, −8.5, and −8.8 kcal/mol. Several active sites in the targeted protein, including Cys145, His41, Met49, Glu66, and Met165, were found to interact with the top three candidate compounds. The multiple simulation profile, root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and solvent-accessible surface area values supported the inflexible nature of the docked protein–compound complexes. The toxicity and carcinogenicity profiles were assessed, which showed that epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate had favorable pharmacological properties with no adverse effects. These findings suggest that these compounds could be developed as part of an effective drug development pathway to treat COVID-19.

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

Molecules ◽  
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.

scholarly journals Molecular Dynamics Simulation of Cholera Toxin A-1 Polypeptide

2016 ◽  
Vol 14 (1) ◽  
pp. 188-196 ◽  
Author(s):  
Syed Lal Badshah ◽  
Abdul Naeem Khan ◽  
Yahia Nasser Mabkhot
Keyword(s):  
Molecular Dynamics ◽  
Secondary Structure ◽  
Cholera Toxin ◽  
Root Mean Square ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Toxin A

AbstractA molecular dynamics (MD) simulation study of the enzymatic portion of cholera toxin; cholera toxin A-1 polypeptide (CTA1) was performed at 283, 310 and 323 K. From total energy analysis it was observed that this toxin is stable thermodynamically and these outcomes were likewise confirmed by root mean square deviations (RMSD) investigations. The Cα root mean square fluctuation (RMSF) examinations revealed that there are a number of residues inside CTA1, which can be used as target for designing and synthesizing inhibitory drugs, in order to inactivate cholera toxin inside the human body. The fluctuations in the radius of gyration and hydrogen bonding in CTA1 proved that protein unfolding and refolding were normal routine phenomena in its structure at all temperatures. Solvent accessible surface area study identified the hydrophilic nature of the CTA1, and due to this property it can be a potential biological weapon. The structural identification (STRIDE) algorithm for proteins was successfully used to determine the partially disordered secondary structure of CTA1. On account of this partially disordered secondary structure, it can easily deceive the proteolytic enzymes of the endoplasmic reticulum of host cells.

scholarly journals Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4829
Author(s):  
Sajjad Haider ◽  
Assem Barakat ◽  
Zaheer Ul-Haq
Keyword(s):  
Virtual Screening ◽  
Molecular Dynamic ◽  
Root Mean Square ◽  
Cancer Metastasis ◽  
Pharmacophore Model ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Dynamic Simulations

CXCL12 are small pro-inflammatory chemo-attractant cytokines that bind to a specific receptor CXCR4 with a role in angiogenesis, tumor progression, metastasis, and cell survival. Globally, cancer metastasis is a major cause of morbidity and mortality. In this study, we targeted CXCL12 rather than the chemokine receptor (CXCR4) because most of the drugs failed in clinical trials due to unmanageable toxicities. Until now, no FDA approved medication has been available against CXCL12. Therefore, we aimed to find new inhibitors for CXCL12 through virtual screening followed by molecular dynamics simulation. For virtual screening, active compounds against CXCL12 were taken as potent inhibitors and utilized in the generation of a pharmacophore model, followed by validation against different datasets. Ligand based virtual screening was performed on the ChEMBL and in-house databases, which resulted in successive elimination through the steps of pharmacophore-based and score-based screenings, and finally, sixteen compounds of various interactions with significant crucial amino acid residues were selected as virtual hits. Furthermore, the binding mode of these compounds were refined through molecular dynamic simulations. Moreover, the stability of protein complexes, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and radius of gyration were analyzed, which led to the identification of three potent inhibitors of CXCL12 that may be pursued in the drug discovery process against cancer metastasis.

scholarly journals Fruit Bromelain-Derived Peptide Potentially Restrains the Attachment of SARS-CoV-2 Variants to hACE2: A Pharmacoinformatics Approach

Molecules ◽  
2022 ◽  
Vol 27 (1) ◽  
pp. 260
Author(s):  
Trina Ekawati Tallei ◽  
Fatimawali ◽  
Ahmad Akroman Adam ◽  
Mona M. Elseehy ◽  
Ahmed M. El-Shehawi ◽  
...  
Keyword(s):  
Root Mean Square ◽  
Antiviral Agents ◽  
Md Simulations ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Angiotensin Converting Enzyme 2 ◽  
In Silico Study ◽  
Mean Square Fluctuation ◽  
Binding Residues ◽  
Binding Energy Calculations

Before entering the cell, the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) binds to the human angiotensin-converting enzyme 2 (hACE2) receptor. Hence, this RBD is a critical target for the development of antiviral agents. Recent studies have discovered that SARS-CoV-2 variants with mutations in the RBD have spread globally. The purpose of this in silico study was to determine the potential of a fruit bromelain-derived peptide. DYGAVNEVK. to inhibit the entry of various SARS-CoV-2 variants into human cells by targeting the hACE binding site within the RBD. Molecular docking analysis revealed that DYGAVNEVK interacts with several critical RBD binding residues responsible for the adhesion of the RBD to hACE2. Moreover, 100 ns MD simulations revealed stable interactions between DYGAVNEVK and RBD variants derived from the trajectory of root-mean-square deviation (RMSD), radius of gyration (Rg), and root-mean-square fluctuation (RMSF) analysis, as well as free binding energy calculations. Overall, our computational results indicate that DYGAVNEVK warrants further investigation as a candidate for preventing SARS-CoV-2 due to its interaction with the RBD of SARS-CoV-2 variants.

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

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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