scholarly journals 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 ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 823 ◽  
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.

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

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4589 ◽  
Author(s):  
Taj Mohammad ◽  
Sagar Batra ◽  
Rashmi Dahiya ◽  
Mohammad Hassan Baig ◽  
Irfan Ahmad Rather ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Conformational Changes ◽  
Interaction Analysis ◽  
Interaction Mechanism ◽  
Structural Similarity ◽  
Docking Studies ◽  
Dynamics Simulation ◽  
Cyclin Dependent Kinase ◽  
Pubchem Database ◽  
Cycle Regulation

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.

scholarly journals A Computational Approach with Biological Evaluation: Combinatorial Treatment of Curcumin and Exemestane Synergistically Regulates DDX3 Expression in Cancer Cell Lines

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 857
Author(s):  
Shailima Rampogu ◽  
Seong Min Kim ◽  
Minky Son ◽  
Ayoung Baek ◽  
Chanin Park ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Cell Lines ◽  
Cancer Progression ◽  
Biological Evaluation ◽  
Dynamics Simulation ◽  
Promising Target ◽  
Vitro Analysis ◽  
Combinatorial Treatment

DDX3 belongs to RNA helicase family that demonstrates oncogenic properties and has gained wider attention due to its role in cancer progression, proliferation and transformation. Mounting reports have evidenced the role of DDX3 in cancers making it a promising target to abrogate DDX3 triggered cancers. Dual pharmacophore models were generated and were subsequently validated. They were used as 3D queries to screen the InterBioScreen database, resulting in the selection of curcumin that was escalated to molecular dynamics simulation studies. In vitro anti-cancer analysis was conducted on three cell lines such as MCF-7, MDA-MB-231 and HeLa, which were evaluated along with exemestane. Curcumin was docked into the active site of the protein target (PDB code 2I4I) to estimate the binding affinity. The compound has interacted with two key residues and has displayed stable molecular dynamics simulation results. In vitro analysis has demonstrated that both the candidate compounds have reduced the expression of DDX3 in three cell lines. However, upon combinatorial treatment of curcumin (10 and 20 μM) and exemestane (50 μM) a synergism was exhibited, strikingly downregulating the DDX3 expression and has enhanced apoptosis in three cell lines. The obtained results illuminate the use of curcumin as an alternative DDX3 inhibitor and can serve as a chemical scaffold to design new small molecules.

Insight into the Interaction Mechanism of Nicotine, NNK, and NNN with Cytochrome P450 2A13 Based on Molecular Dynamics Simulation

2019 ◽  
Vol 60 (2) ◽  
pp. 766-776 ◽  
Author(s):  
Jorddy Neves Cruz ◽  
Mozaniel Santana de Oliveira ◽  
Sebastião Gomes Silva ◽  
Antonio Pedro da Silva Souza Filho ◽  
Daniel Santiago Pereira ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Cytochrome P450 ◽  
Molecular Dynamics Simulation ◽  
Interaction Mechanism ◽  
Dynamics Simulation ◽  
Insight Into

Study the Interaction Mechanism and Mechanical Properties of PVA/HA by a Molecular Dynamics Simulation

2017 ◽  
Vol 737 ◽  
pp. 299-306
Author(s):  
Ming Ming Yang ◽  
Ya Nen Wang ◽  
Qing Hua Wei ◽  
Wei Hong Chai ◽  
Sheng Min Wei
Keyword(s):  
Mechanical Properties ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Binding Energy ◽  
Pair Correlation ◽  
Interaction Mechanism ◽  
Crystallographic Plane ◽  
Dynamics Simulation ◽  
Ionic Bonds ◽  
Crystallographic Planes

To investigate the interaction mechanism of PVA on the surface of HA, the molecular dynamics simulation was applied to simulate and calculate the binding energy between PVA of different monomers and HA crystallographic planes (001), (100) and (110), and then the mechanical properties and radial distribution function of the PVA/HA(110) system were calculated and analyzed. The results show that HA (110) has the higher binding energy with PVA than that of HA (001) and (100). The binding energy and the Young’s modulus of HA(110)/PVA system increase with the rising of PVA monomer number at the same crystallographic plane in a certain range, however, the descending trend takes place while monomers number reaching a certain value. This change trend is relating to the effective contact between two single components. By calculating the pair correlation function of HA(110)/PVA, there is a strong interaction between HA crystallographic plane (110) and PVA, it is mainly derived from the hydrogen bonds between O atoms of PVA and H atoms in HA crystal, besides, the ionic bonds interactions existing between OaandCa.

Sign in / Sign up

Export Citation Format

Share Document