Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy

Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. First, we retrieved all compounds from the PubChem database having at least 90% structural similarity with the known CDK2 inhibitors. The selected compounds were subjected to structure-based molecular docking studies to investigate their pattern of interaction and estimate their binding affinities with CDK2. Selected compounds were further filtered out based on their physicochemical and ADMET properties. Detailed interaction analysis revealed that selected compounds interact with the functionally important residues of the active site pocket of CDK2. All-atom molecular dynamics simulation was performed to evaluate conformational changes, stability and the interaction mechanism of CDK2 in-complex with the selected compound. We found that binding of 6-N,6-N-dimethyl-9-(2-phenylethyl)purine-2,6-diamine stabilizes the structure of CDK2 and causes minimal conformational change. Finally, we suggest that the compound (PubChem ID 101874157) would be a promising scaffold to be further exploited as a potential inhibitor of CDK2 for therapeutic management of cancer after required validation.

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Virtual Screening Approach to Identify High-Affinity Inhibitors of Serum and Glucocorticoid-Regulated Kinase 1 among Bioactive Natural Products: Combined Molecular Docking and Simulation Studies

Molecules ◽

10.3390/molecules25040823 ◽

2020 ◽

Vol 25 (4) ◽

pp. 823 ◽

Cited By ~ 6

Author(s):

Taj Mohammad ◽

Shiza Siddiqui ◽

Anas Shamsi ◽

Mohamed F. Alajmi ◽

Afzal Hussain ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Cancer Progression ◽

Conformational Changes ◽

High Throughput Screening ◽

Transcriptional Control ◽

Interaction Analysis ◽

Interaction Mechanism ◽

Principal Component ◽

Dynamics Simulation

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase that works under acute transcriptional control by several stimuli, including serum and glucocorticoids. It plays a significant role in the cancer progression and metastasis, as it regulates inflammation, apoptosis, hormone release, neuro-excitability, and cell proliferation. SGK1 has recently been considered as a potential drug target for cancer, diabetes, and neurodegenerative diseases. In the present study, we have performed structure-based virtual high-throughput screening of natural compounds from the ZINC database to find potential inhibitors of SGK1. Initially, hits were selected based on their physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and other drug-like properties. Afterwards, PAINS filter, binding affinities estimation, and interaction analysis were performed to find safe and effective hits. We found four compounds bearing appreciable binding affinity and specificity towards the binding pocket of SGK1. The docking results were complemented by all-atom molecular dynamics simulation for 100 ns, followed by MM/PBSA, and principal component analysis to investigate the conformational changes, stability, and interaction mechanism of SGK1 in-complex with the selected compound ZINC00319000. Molecular dynamics simulation results suggested that the binding of ZINC00319000 stabilizes the SGK1 structure, and it leads to fewer conformational changes. In conclusion, the identified compound ZINC00319000 might be further exploited as a scaffold to develop promising inhibitors of SGK1 for the therapeutic management of associated diseases, including cancer.

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Structural and Dynamic Characterizations Highlight the Deleterious Role of SULT1A1 R213H Polymorphism in Substrate Binding

International Journal of Molecular Sciences ◽

10.3390/ijms20246256 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6256 ◽

Cited By ~ 7

Author(s):

Raju Dash ◽

Md. Chayan Ali ◽

Nayan Dash ◽

Md. Abul Kalam Azad ◽

S. M. Zahid Hosen ◽

...

Keyword(s):

Binding Energy ◽

Cancer Progression ◽

Conformational Changes ◽

Substrate Binding ◽

Dynamics Simulation ◽

Loss Of Function ◽

Functional Consequences ◽

Binding Energy Analysis ◽

Exogenous Compounds

Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind the loss-of-function of SULT1A1, the present study deployed molecular dynamics simulation to get insights into changes in the conformation and binding energy. The dynamics scenario of SULT1A1 in both wild and mutated types as well as with and without ligand showed that R213H induced local conformational changes, especially in the substrate-binding loop rather than impairing overall stability of the protein structure. The higher conformational changes were observed in the loop3 (residues, 235–263), turning loop conformation to A-helix and B-bridge, which ultimately disrupted the plasticity of the active site. This alteration reduced the binding site volume and hydrophobicity to decrease the binding affinity of the enzyme to substrates, which was highlighted by the MM-PBSA binding energy analysis. These findings highlight the key insights of structural consequences caused by R213H mutation, which would enrich the understanding regarding the role of SULT1A1 mutation in cancer development and also xenobiotics management to individuals in the different treatment stages.

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Evaluation of binding and inhibition mechanism of dietary phytochemicals with sphingosine kinase 1: Towards targeted anticancer therapy

Scientific Reports ◽

10.1038/s41598-019-55199-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 16

Author(s):

Preeti Gupta ◽

Taj Mohammad ◽

Rashmi Dahiya ◽

Sonam Roy ◽

Omar Mohammed Ali Noman ◽

...

Keyword(s):

Conformational Changes ◽

Inflammatory Diseases ◽

Sphingosine Kinase ◽

Competitive Inhibitor ◽

Docking Studies ◽

Dynamics Simulation ◽

Inhibition Mechanism ◽

Stable Complex ◽

Sphingosine Kinase 1 ◽

Dietary Phytochemicals

AbstractSphingosine kinase 1 (SphK1) has recently gained attention as a potential drug target for its association with cancer and other inflammatory diseases. Here, we have investigated the binding affinity of dietary phytochemicals viz., ursolic acid, capsaicin, DL-α tocopherol acetate, quercetin, vanillin, citral, limonin and simvastatin with the SphK1. Docking studies revealed that all these compounds bind to the SphK1 with varying affinities. Fluorescence binding and isothermal titration calorimetric measurements suggested that quercetin and capsaicin bind to SphK1 with an excellent affinity, and significantly inhibits its activity with an admirable IC50 values. The binding mechanism of quercetin was assessed by docking and molecular dynamics simulation studies for 100 ns in detail. We found that quercetin acts as a lipid substrate competitive inhibitor, and it interacts with important residues of active-site pocket through hydrogen bonds and other non-covalent interactions. Quercetin forms a stable complex with SphK1 without inducing any significant conformational changes in the protein structure. In conclusion, we infer that quercetin and capsaicin provide a chemical scaffold to develop potent and selective inhibitors of SphK1 after required modifications for the clinical management of cancer.

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Ellagic Acid Controls Cell Proliferation and Induces Apoptosis in Breast Cancer Cells via Inhibition of Cyclin-Dependent Kinase 6

International Journal of Molecular Sciences ◽

10.3390/ijms21103526 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3526 ◽

Cited By ~ 8

Author(s):

Mohd Yousuf ◽

Anas Shamsi ◽

Parvez Khan ◽

Mohd Shahbaaz ◽

Mohamed F. AlAjmi ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Ellagic Acid ◽

Dynamics Simulation ◽

Breast Cancer Cell Lines ◽

Binding Affinities ◽

Cyclin Dependent Kinase ◽

Binding Studies ◽

Fluorescence Binding

Cyclin-Dependent Kinase 6 (CDK6) plays an important role in cancer progression, and thus, it is considered as an attractive drug target in anticancer therapeutics. This study presents an evaluation of dietary phytochemicals, capsaicin, tocopherol, rosmarinic acid, ursolic acid, ellagic acid (EA), limonene, caffeic acid, and ferulic acid for their potential to inhibit the activity of CDK6. Molecular docking and fluorescence binding studies revealed appreciable binding affinities of these compounds to the CDK6. Among them, EA shows the highest binding affinity for CDK6, and thus a molecular dynamics simulation study of 200 ns was performed to get deeper insights into the binding mechanism and stability of the CDK6-EA complex. Fluorescence binding studies revealed that EA binds to the CDK6 with a binding constant of K = 107 M−1 and subsequently inhibits its enzyme activity with an IC50 value of 3.053 µM. Analysis of thermodynamic parameters of CDK6-EA complex formation suggested a hydrophobic interaction driven process. The treatment of EA decreases the colonization of cancer cells and induces apoptosis. Moreover, the expression of CDK6 has been downregulated in EA-treated human breast cancer cell lines. In conclusion, this study establishes EA as a potent CDK6 inhibitor that can be further evaluated in CDK6 directed anticancer therapies.

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Homology Modeling of Mus Musculus CDK5 and Molecular Docking Studies with Flavonoids

International Journal of Pharmaceutical and Clinical Research ◽

10.25258/ijpcr.v9i6.8779 ◽

2017 ◽

Vol 9 (6) ◽

Author(s):

Sowmya Suri ◽

Rumana Waseem ◽

Seshagiri Bandi ◽

Sania Shaik

Keyword(s):

Molecular Docking ◽

3D Model ◽

Structural Features ◽

Docking Studies ◽

Amino Acid Residues ◽

Cyclin Dependent Kinase ◽

Ligand Complex ◽

Ligand Interaction ◽

Molecular Docking Studies ◽

Cyclin Dependent Kinase 5

A 3D model of Cyclin-dependent kinase 5 (CDK5) (Accession Number: Q543f6) is generated based on crystal structure of P. falciparum PFPK5-indirubin-5-sulphonate ligand complex (PDB ID: 1V0O) at 2.30 Å resolution was used as template. Protein-ligand interaction studies were performed with flavonoids to explore structural features and binding mechanism of flavonoids as CDK5 (Cyclin-dependent kinase 5) inhibitors. The modelled structure was selected on the basis of least modeler objective function. The model was validated by PROCHECK. The predicted 3D model is reliable with 93.0% of amino acid residues in core region of the Ramachandran plot. Molecular docking studies with flavonoids viz., Diosmetin, Eriodictyol, Fortuneletin, Apigenin, Ayanin, Baicalein, Chrysoeriol and Chrysosplenol-D with modelled protein indicate that Diosmetin is the best inhibitor containing docking score of -8.23 kcal/mol. Cys83, Lys89, Asp84. The compound Diosmetin shows interactions with Cys83, Lys89, and Asp84.

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In silico Discovery of Resveratrol Analogues as Potential Agents in Treatment of Metabolic Disorders

Current Pharmaceutical Design ◽

10.2174/1381612825666191029095252 ◽

2019 ◽

Vol 25 (35) ◽

pp. 3776-3783

Author(s):

Nebojša Pavlović ◽

Maja Đanić ◽

Bojan Stanimirov ◽

Svetlana Goločorbin-Kon ◽

Karmen Stankov ◽

...

Keyword(s):

In Silico ◽

Metabolic Disorders ◽

Partial Agonist ◽

Aqueous Solubility ◽

Structural Similarity ◽

Data Bank ◽

Docking Studies ◽

Binding Energies ◽

Molegro Virtual Docker ◽

Ppar Γ

Background: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which opens up the possibility for its use in the treatment of metabolic disorders. Considering the poor bioavailability of resveratrol, particularly due to its low aqueous solubility, we aimed to identify analogues of resveratrol with improved pharmacokinetic properties and higher binding affinities towards PPAR-γ. Methods: 3D structures of resveratrol and its analogues were retrieved from ZINC database, while PPAR-γ structure was obtained from Protein Data Bank. Docking studies were performed using Molegro Virtual Docker software. Molecular descriptors relevant to pharmacokinetics were calculated from ligand structures using VolSurf+ software. Results: Using structural similarity search method, 56 analogues of resveratrol were identified and subjected to docking analyses. Binding energies were ranged from -136.69 to -90.89 kcal/mol, with 16 analogues having higher affinities towards PPAR-γ in comparison to resveratrol. From the calculated values of SOLY descriptor, 23 studied compounds were shown to be more soluble in water than resveratrol. However, only two tetrahydroxy stilbene derivatives, piceatannol and oxyresveratrol, had both better solubility and affinity towards PPAR-γ. These compounds also had more favorable ADME profile, since they were shown to be more metabolically stable and wider distributed in body than resveratrol. Conclusion: Piceatannol and oxyresveratrol should be considered as potential lead compounds for further drug development. Although experimental validation of obtained in silico results is required, this work can be considered as a step toward the discovery of new natural and safe drugs in treatment of metabolic disorders.

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Molecular Dynamics Simulation and Docking Studies of Selenocyanate Derivatives as Anti-Leishmanial Agents

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207319666160907102235 ◽

2016 ◽

Vol 19 (10) ◽

Cited By ~ 3

Author(s):

Maryam Iman ◽

Hamid Bakhtiari Kaboutaraki ◽

Rahim Jafari ◽

Seyed Ayoub Hosseini ◽

Abolghasem Moghimi ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Docking Studies ◽

Dynamics Simulation

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In Silico Studies on Anti-Stress Compounds of Ethanolic Root Extract of Hemidesmus indicus L.

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666191211152754 ◽

2020 ◽

Vol 21 (6) ◽

pp. 502-515

Author(s):

Jayasimha R. Daddam ◽

Basha Sreenivasulu ◽

Katike Umamahesh ◽

Kotha Peddanna ◽

Dowlathabad M. Rao

Keyword(s):

Conventional Medicine ◽

Herbal Medicines ◽

Ethanolic Extract ◽

Data Bank ◽

Docking Studies ◽

Dynamics Simulation ◽

Alternative Methods ◽

Root Extract ◽

Hemidesmus Indicus ◽

In Silico Studies

Background: Alternative medicine is available for those diseases which cannot be treated by conventional medicine. Ayurveda and herbal medicines are important alternative methods in which the treatment is done with extracts of different medicinal plants. This work is concerned with the evaluation of anti-stress bioactive compounds from the ethanolic root extract of Hemidesmus indicus. Methods: Gas chromatography and Mass Spectrum studies are used to identify the compounds present in the ethanolic extract based on the retention time, area. In order to perform docking studies, Vasopressin model is generated using modeling by Modeller 9v7. Vasopressin structure is developed based on the crystal structure of neurophysin-oxytocin from Bos taurus (PDB ID: 1NPO_A) collected from the PDB data bank. Using molecular dynamics simulation methods, the final predicted structure is obtained and further analyzed by verifying 3D and PROCHECK programs, confirmed that the final model is reliable. The identified compounds are docked to vasopressin for the prediction of anti-stress activity using GOLD 3.0.1 software. Results: The predicted model of Vasopressin structure is stabilized and confirmed that it is a reliable structure for docking studies. The results indicated ARG4, THR7, ASP9, ASP26, ALA32, ALA 80 in Vasopressin are important determinant residues in binding as they have strong hydrogen bonding with phytocompounds. Among the 21 phytocompounds identified and docked, molecule Deoxiinositol, pentakis- O-(trimethylsilyl) showed the best docking results with Vasopressin. Conclusion: The identified compounds were used for anti-stress activity by insilico method with Vasopressin which plays an important role in causing stress and hence selected for inhibitory studies with phytocompounds. The phytocompounds are inhibiting vasopressin through hydrogen bodings and are important in protein-ligand interactions. Docking results showed that out of twenty-one compounds, Deoxiinositol, pentakis-O-(trimethylsilyl) showed best docking energy to the Vasopressin.

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Synthesis, Docking Studies into CDK-2 and Anticancer Activity of New Derivatives Based Pyrimidine Scaffold and Their Derived Glycosides

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190312165717 ◽

2019 ◽

Vol 19 (13) ◽

pp. 1093-1110 ◽

Cited By ~ 5

Author(s):

Adel A.H. Abdel Rahman ◽

Ibrahim F. Nassar ◽

Amira K.F. Shaban ◽

Dina S. EL-Kady ◽

Hanem M. Awad ◽

...

Keyword(s):

Anticancer Activity ◽

Human Liver ◽

Docking Studies ◽

Cyclin Dependent Kinase ◽

Binding Interaction ◽

Enzyme Active Site ◽

Human Liver Cancer ◽

Amino Derivatives ◽

Activity Behavior ◽

Derivatives Of

Background & Objective:New diaryl-substituted pyrimidinedione compounds, their thioxo derivatives as well as their bicyclic thiazole compounds were synthesized and characterized.Methods:The glycosylamino derivatives of the synthesized disubstituted derivatives of the pyrimidine scaffold were also prepared via reaction of the N3-amino derivatives with a number of monosaccharides followed by acetylation.Results:The anticancer activity of the synthesized compounds was studied against human liver cancer (HepG2) and RPE-1cell lines. Compounds 2a, 2b, 3a and 12 showed potent activities with IC50 results comparable to that of doxorubicin.Conclusion:Docking investigations into Cyclin-dependent kinase 2 (CDK-2) enzyme, a potential target for cancer medication, were also reported showing the possible binding interaction into the enzyme active site to support their activity behavior.

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Hydroxyurea—The Good, the Bad and the Ugly

Genes ◽

10.3390/genes12071096 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1096

Author(s):

Marcelina W. Musiałek ◽

Dorota Rybaczek

Keyword(s):

Cancer Progression ◽

Specific Interaction ◽

Interaction Mechanism ◽

Myeloproliferative Disorders ◽

Prolonged Treatment ◽

Actual State ◽

Cytotoxic Effects ◽

Factors Affecting ◽

Cell Cycles ◽

Practical Applications

Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the cycle by inducing replication stress. It is a well-known and widely used drug, one which has proved to be effective in treating chronic myeloproliferative disorders and which is considered a staple agent in sickle anemia therapy and—recently—a promising factor in preventing cognitive decline in Alzheimer’s disease. The reversibility of HU-induced replication inhibition also makes it a common laboratory ingredient used to synchronize cell cycles. On the other hand, prolonged treatment or higher dosage of hydroxyurea causes cell death due to accumulation of DNA damage and oxidative stress. Hydroxyurea treatments are also still far from perfect and it has been suggested that it facilitates skin cancer progression. Also, recent studies have shown that hydroxyurea may affect a larger number of enzymes due to its less specific interaction mechanism, which may contribute to further as-yet unspecified factors affecting cell response. In this review, we examine the actual state of knowledge about hydroxyurea and the mechanisms behind its cytotoxic effects. The practical applications of the recent findings may prove to enhance the already existing use of the drug in new and promising ways.

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