A Study of the Mechanism of Binding between Neratinib and MAD2L1 Based on Molecular Simulation and Multi-spectroscopy Methods

2020 ◽  
Vol 25 (40) ◽  
pp. 4287-4295 ◽  
Author(s):  
Guangya Zhou ◽  
Manman Zhao ◽  
Ruirui Liang ◽  
Jiayang Xie ◽  
Xinyi Chen ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Conformational Change ◽  
Binding Sites ◽  
Biological Function ◽  
Kinase Inhibitor ◽  
Three Dimensional ◽  
Binding Mode ◽  
Physiological Conditions ◽  
Medicinal Value ◽  
Potential Binding

Background: Nilatinib is an irreversible tyrosine kinase inhibitor, which is used in the treatment of some kinds of cancer. To study the interaction between Neratinib and MAD2L1, a potential tumor target, is of guiding significance for enriching the medicinal value of Neratinib. Method: The binding mechanism between Mitotic arrest deficient 2-like protein 1 (MAD2L1) and Neratinib under simulative physiological conditions was investigated by molecule simulation and multi-spectroscopy approaches. Results: Molecular docking showed the most possible binding mode of Neratinib-MAD2L1 and the potential binding sites and interaction forces of the interaction between MAD2L1 and Neratinib. Fluorescence spectroscopy experiments manifested that Neratinib could interact with MAD2L1 and form a complex by hydrogen bond and van der Waals interaction. These results were consistent with the conclusions obtained from molecular docking. In addition, according to Synchronous fluorescence and three-dimensional fluorescence results, Neratinib might lead to the conformational change of MAD2L1, which may affect the biological functions of MAD2L1. Conclusion: This study indicated that Neratinib could interact with MAD2L1 and lead to the conformational change of MAD2L1. These works provide helpful insights for the further study of biological function of MAD2L1 and novel pharmacological utility of Neratinib.

Binding mode of the tyrosine kinase inhibitor bosutinib (SKI-606) to Abl kinase

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7049-7049
Author(s):  
S. Soverini ◽  
G. Tasco ◽  
T. Grafone ◽  
S. Colarossi ◽  
A. Gnani ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Three Dimensional ◽  
Binding Mode ◽  
Kinase Domain ◽  
Pharmacological Therapy ◽  
Van Der Waals Interactions ◽  
Three Dimensional Model ◽  
Abl Kinase ◽  
Closed Conformation ◽  
Docking Approach

7049 Background: Bosutinib (SKI-606) is a 4-anilino-3-quinolinecarbonitrile Src/Abl kinase inhibitor. The crystal structure of Abl kinase domain in complex with bosutinib has not yet been determined and the mode of binding of this inhibitor is therefore unknown. Methods: In the present study, we used a molecular docking approach to investigate the following: a) Which Abl conformation(s) bosutinib is more likely to bind? b) Which Abl residues are likely to be involved in bosutinib binding? c) Which imatinib-resistant Abl mutants bosutinib is likely to be active against? A three-dimensional model of bosutinib was generated by Chemsketch ( http://www.acdlabs.com ). Modelling of the human Abl kinase in its inactive (closed) conformation was performed with the software Modeller, v7.7 ( http://salilab.org/modeller ) adopting the highly related Mus musculus Abl homologue as a template structure (PDB entry: 1OPJ , 0.175nm resolution). Active (open) Abl conformation is available as PDB entry 1OPL . Flexible docking of bosutinib to Abl was performed with Autodock v3.0 ( http://www.scripps.edu/mb/olson ). Results: Our binding hypothesis predicts that a) similarly to IM, the interaction between bosutinib and Abl seems to be more stable when the latter is in its inactive (closed) conformation; b) 21 Abl residues (including Y253, T315, F317 and F359 among others) surround bosutinib and engage H-bonds or Van der Waals interactions; c) bosutinib is likely to retain the ability to bind and inhibit the IM-resistant Y253H, M351T, F359V, F317L and E255V Abl mutants. In contrast, bosutinib binding to E255K and T315I mutants is predicted to be less efficient. Detailed models will be presented. Conclusions: Bosutinib is a promising second-line treatment for Ph+ leukemia patients harbouring several IM-resistant Abl mutations. The T315I remains the biggest hurdle for pharmacological therapy of Ph+ leukemias. Supported by European LeukemiaNet, AIRC, AIL, COFIN and FIRB projects, and by Fondazione del Monte di Bologna e Ravenna. No significant financial relationships to disclose.

Study of the Interaction of Ciprofloxacin and Sparfloxacin with Biomolecules by Spectral, Electrochemical and Molecular Docking Methods

2018 ◽  
Vol 78 ◽  
pp. 1-29 ◽  
Author(s):  
N. Rajendiran ◽  
M. Suresh
Keyword(s):  
Cyclic Voltammetry ◽  
Molecular Docking ◽  
Binding Sites ◽  
Electrostatic Interactions ◽  
Fluorescence Spectra ◽  
Blue Shift ◽  
Binding Mode ◽  
Interaction Processes ◽  
Good Accordance ◽  
Uv Visible

Interactions of ciprofloxacin and sparfloxacin with different biomolecules (DNA, RNA and BSA) are investigated by UV–Visible spectroscopy, fluorescence spectroscopy, cyclic voltammetry and molecular docking methods. Upon increasing the concentration of the biomolecules, the absorption maxima of ciprofloxacin and sparfloxacin are red shifted in the aqueous solutions whereas red or blue shift noticed in the fluorescence spectra. The negative free energy changes suggest that the interaction processes are spontaneous. Cyclic voltammetry results suggested that when the drug concentration is increased, the anodic electrode potential increased. Molecular docking results showed that hydrophobic forces, electrostatic interactions, and hydrogen bonds played vital roles in the interaction drugs with biomolecules. The molecular docking calculation clarifies the binding mode and the binding sites are in good accordance with the experiment results.

scholarly journals Three-dimensional structures ofPlasmodium falciparumspermidine synthase with bound inhibitors suggest new strategies for drug design

2015 ◽  
Vol 71 (3) ◽  
pp. 484-493 ◽  
Author(s):  
Janina Sprenger ◽  
Bo Svensson ◽  
Jenny Hålander ◽  
Jannette Carey ◽  
Lo Persson ◽  
...  
Keyword(s):  
Binding Sites ◽  
Drug Targets ◽  
Enzymatic Reaction ◽  
Three Dimensional ◽  
Binding Mode ◽  
Polyamine Biosynthesis ◽  
X Ray ◽  
X Ray Crystallography ◽  
Substrate Binding Sites ◽  
New Strategies

The enzymes of the polyamine-biosynthesis pathway have been proposed to be promising drug targets in the treatment of malaria. Spermidine synthase (SpdS; putrescine aminopropyltransferase) catalyzes the transfer of the aminopropyl moiety from decarboxylatedS-adenosylmethionine to putrescine, leading to the formation of spermidine and 5′-methylthioadenosine (MTA). In this work, X-ray crystallography was used to examine ligand complexes of SpdS from the malaria parasitePlasmodium falciparum(PfSpdS). Five crystal structures were determined ofPfSpdS in complex with MTA and the substrate putrescine, with MTA and spermidine, which was obtained as a result of the enzymatic reaction taking place within the crystals, with dcAdoMet and the inhibitor 4-methylaniline, with MTA and 4-aminomethylaniline, and with a compound predicted in earlierin silicoscreening to bind to the active site of the enzyme, benzimidazol-(2-yl)pentan-1-amine (BIPA). In contrast to the other inhibitors tested, the complex with BIPA was obtained without any ligand bound to the dcAdoMet-binding site of the enzyme. The complexes with the aniline compounds and BIPA revealed a new mode of ligand binding toPfSpdS. The observed binding mode of the ligands, and the interplay between the two substrate-binding sites and the flexible gatekeeper loop, can be used in the design of new approaches in the search for new inhibitors of SpdS.

Molecular Interactions of Fullerene-Based Derivatives and SARS-CoV-2

2020 ◽  
Author(s):  
Alaa El-DinA. Gawad ◽  
Ahmed M. Bayoumy ◽  
Medhat A. Ibrahim
Keyword(s):  
Molecular Docking ◽  
Hydrogen Bonds ◽  
Binding Sites ◽  
Electrostatic Interactions ◽  
Binding Mode ◽  
Spike Protein ◽  
Promising Candidate ◽  
Binding Behavior ◽  
Computer Aided ◽  
Differential Binding

Abstract There are no expedient proven to stop the outbreak of SARS-CoV-2 at this phase. This leads to diversity of endeavors to find out the effective drug or vaccine. One of these possibilities is to exploit the unique characteristics of fullerene-based derivatives. A computer-aided method (molecular docking) was applied to assess the differential binding behavior of these compounds and determining hydrophobic forces, electrostatic interactions, and hydrogen bonds played vital roles in the interactions with SARS-CoV-2 spike protein. The molecular docking calculation clarifies the binding mode and the binding sites may facilitate the development of new or improved therapeutic regimes effective against COVID-19. Fulleropyrrolidine-NH2 seems to be promising candidate for interacting with SARS-CoV-2 binding site.

scholarly journals Alpha-Glucosidase Inhibitory Assay-Screened Isolation and Molecular Docking Model from Bauhinia pulla Active Compounds

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5970
Author(s):  
Sukanya Dej-adisai ◽  
Ichwan Ridwan Rais ◽  
Chatchai Wattanapiromsakul ◽  
Thanet Pitakbut
Keyword(s):  
Molecular Docking ◽  
Methyl Ether ◽  
Inhibitory Activity ◽  
Binding Sites ◽  
Chemical Constituents ◽  
Spectroscopic Techniques ◽  
Leaf Extracts ◽  
Docking Model ◽  
Potential Binding ◽  
Alpha Glucosidase

The aim of this research was to establish the constituents of Bauhinia pulla as anti-diabetic agents. A phytochemistry analysis was conducted by chromatographic and spectroscopic techniques. The alpha-glucosidase inhibitory assay screening resulted in the isolation of eight known compounds of quercetin, quercitrin, luteolin, 5-deoxyluteolin, 4-methyl ether isoliquiritigenin, 3,2′,4′-trihydroxy-4-methoxychalcone, stigmasterol and β-sitosterol. Ethanol leaf extracts showed potential effects, which led to a strong inhibitory activity of isolated quercetin at 138.95 µg/mL and 5.41 µg/mL of IC50, respectively. The docking confirmed that flavonoids and chalcones had the same potential binding sites and responsibilities for their activity. This study was the first report of Bauhinia pulla chemical constituents and its alpha-glucosidase inhibition.

Homology Modeling of Aeromonas hydrophila Laccase and its Molecular Docking with the 2,5-Xylidine

2013 ◽  
Vol 798-799 ◽  
pp. 83-86
Author(s):  
Dong Xia Du ◽  
Shi Ping Shan ◽  
De Yuan Zhang ◽  
Yue Lin He
Keyword(s):  
Molecular Docking ◽  
Homology Modeling ◽  
Aeromonas Hydrophila ◽  
Three Dimensional ◽  
Industrial Effluents ◽  
Binding Pocket ◽  
Binding Mode ◽  
Major Effect ◽  
Dimensional Structure ◽  
Three Dimensional Structure

Laccases belonging to multicopper oxidase family oxidize a broad range of reducing substrates, especially industrial effluents-derived polyphenols, which causing major effect on human health as well as environment. In order to investigate the molecular mechanism of interaction between laccase and its substrate, it is a good idea to analyze three-dimensional structure of laccase. Based on crystal structure ofEscherichia colilaccase CueO, the three-dimensional structure ofAeromonas hydrophilaLaccase (Ah-lac) was constructed by homology modeling and further evaluated using PROSA energy and ERRAT. The substrate binding site in Ah-lac was predicted and the binding mode of 2,5-Xylidine as a putative ligand to Ah-lac was presented using molecular docking. The residues of Met378 and His382 in the binding pocket are responsible for the interactions with 2,5-Xylidine via two hydrogen bonds. The two residues could be important for substrate recognition.

scholarly journals In-silico molecular docking study of novel derivatives of erlotinib in glioma

2020 ◽  
pp. 34-38
Author(s):  
Deepika Tripathi ◽  
Sabiha Imran
Keyword(s):  
Molecular Docking ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Control Cell ◽  
Antineoplastic Agent ◽  
Binding Mode ◽  
Atomic Scale ◽  
Molecular Docking Study ◽  
Quinazoline Derivative ◽  
Derivatives Of

Gliomas are primary brain tumours arises from the glial cells. Gliomas associated risk factor depend upon its degree of stage and grade. Erlotinib is a quinazoline derivative and antineoplastic agent that capacities as a Protein Kinase Inhibitor for Epidermal growth factor receptor (EGFR) related tyrosine kinase and widely used for treating non-small cell carcinoma. Erlotinib, (a tyrosine kinase inhibitor) has been found in the glioblastoma. ErbB (EGF family receptor tyrosine kinase) established to control cell survival, proliferation, migration, and differentiation. The ErbB receptor accounts for the restricted and redundant functions in the maintenance of tissues in adult mammals. Newly discovered drug targets and personalised treatments could be used to identify the characteristics of any individual’s tumorigenesis. To see the binding mode of deferent classes of erlotinib carefully chosen based on the structural comparison, we employed simulated screening and molecular docking based on the theory of evolution. The study consists of a simulated screening of around 3200 molecular derivatives of erlotinib and their molecular docking using a Lamarckian genetic algorithm. Molecular docking results showed binding energy ranging from -12.15 kcal/mol to -1.17 kcal/mol. Top 10 best-docked proteins were analyzed using UCSF Chimera and finding discovered the complicated atomic-scale properties between ligand and the target protein. Further wet lab study requires to study the actual binding as binding mode provided. To identify new inhibitors of EGFR with higher potency and specificity, additional information is needed for future designs molecules.

Conformation of Ribosomes from Escherichia Coli

1974 ◽  
Vol 32 ◽  
pp. 210-211
Author(s):  
M. Boublik ◽  
W. Hellmann ◽  
F. Jenkins
Keyword(s):  
Binding Sites ◽  
Ribosomal Proteins ◽  
Fluorescent Dyes ◽  
Protein Biosynthesis ◽  
Three Dimensional ◽  
Spatial Arrangement ◽  
Dimensional Structure ◽  
Complete Understanding ◽  
And Function

The present knowledge of the three-dimensional structure of ribosomes is far too limited to enable a complete understanding of the various roles which ribosomes play in protein biosynthesis. The spatial arrangement of proteins and ribonuclec acids in ribosomes can be analysed in many ways. Determination of binding sites for individual proteins on ribonuclec acid and locations of the mutual positions of proteins on the ribosome using labeling with fluorescent dyes, cross-linking reagents, neutron-diffraction or antibodies against ribosomal proteins seem to be most successful approaches. Structure and function of ribosomes can be correlated be depleting the complete ribosomes of some proteins to the functionally inactive core and by subsequent partial reconstitution in order to regain active ribosomal particles.

Design, Synthesis, Molecular Docking and Biological Evaluation of 1-(benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol Derivatives as Antiproliferative Agents

2019 ◽  
Vol 16 (10) ◽  
pp. 837-845
Author(s):  
Sandhya Jonnala ◽  
Bhaskar Nameta ◽  
Murthy Chavali ◽  
Rajashaker Bantu ◽  
Pallavi Choudante ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Mouse Skin ◽  
Coupling Reaction ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Design Synthesis

A class of 1-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol derivatives (4a-t) has been synthesized in good yields through a three component coupling reaction. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against five cell lines such as DU145 (human prostate cancer), MDA-MB-B231 (human breast cancer), SKOV3 (human ovarian cancer), B16-F10 (mouse skin melanoma) and CHO-K1 (Chinese hamster ovary cells), a noncancerous cell line. In vitro inhibitory activity indicates that compounds 4a, 4b, 4c, 4d, 4g, 4j, and 4o exhibited potent anti-proliferative behavior. Among them, compounds 4g, 4j and 4o found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking facilitates to investigate the probable binding mode and key active site interactions in tubulins α and β proteins. The docking results are complementary to experimental results.

3D-QSAR Studies of S-DABO Derivatives as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

2019 ◽  
Vol 16 (8) ◽  
pp. 868-881
Author(s):  
Yueping Wang ◽  
Jie Chang ◽  
Jiangyuan Wang ◽  
Peng Zhong ◽  
Yufang Zhang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Three Dimensional ◽  
Predictive Ability ◽  
3D Qsar ◽  
Binding Mode ◽  
Quantitative Structure Activity Relationship ◽  
Field Analysis ◽  
Reverse Transcriptase Inhibitors ◽  
Qsar Studies ◽  
Hiv 1

Background: S-dihydro-alkyloxy-benzyl-oxopyrimidines (S-DABOs) as non-nucleoside reverse transcriptase inhibitors have received considerable attention during the last decade due to their high potency against HIV-1. Methods: In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) of a series of 38 S-DABO analogues developed in our lab was studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The Docking/MMFF94s computational protocol based on the co-crystallized complex (PDB ID: 1RT2) was used to determine the most probable binding mode and to obtain reliable conformations for molecular alignment. Statistically significant CoMFA (q2=0.766 and r2=0.949) and CoMSIA (q2=0.827 and r2=0.974) models were generated using the training set of 30 compounds on the basis of hybrid docking-based and ligand-based alignment. Results: The predictive ability of CoMFA and CoMSIA models was further validated using a test set of eight compounds with predictive r2 pred values of 0.843 and 0.723, respectively. Conclusion: The information obtained from the 3D contour maps can be used in designing new SDABO derivatives with improved HIV-1 inhibitory activity.

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