scholarly journals Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer

Genes ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 34
Author(s):  
Humaira Ismatullah ◽  
Ishrat Jabeen ◽  
Muhammad Tariq Saeed
Keyword(s):  
Cell Proliferation ◽  
Hydrogen Bond ◽  
Cell Death ◽  
Molecular Docking ◽  
Cancer Progression ◽  
Regulatory Network ◽  
Hydroxyl Group ◽  
Docking Simulations ◽  
Cellular Processes ◽  
Hydrogen Bond Interactions

Inositol trisphosphate receptor (IP3R) mediated Ca+2 signaling is essential in determining the cell fate by regulating numerous cellular processes, including cell division and cell death. Despite extensive studies about the characterization of IP3R in cancer, the underlying molecular mechanism initiating the cell proliferation and apoptosis remained enigmatic. Moreover, in cancer, the modulation of IP3R in downstream signaling pathways, which control oncogenesis and cancer progression, is not well characterized. Here, we constructed a biological regulatory network (BRN), and describe the remodeling of IP3R mediated Ca2+ signaling as a central key that controls the cellular processes in cancer. Moreover, we summarize how the inhibition of IP3R affects the deregulated cell proliferation and cell death in cancer cells and results in the initiation of pro-survival responses in resistance of cell death in normal cells. Further, we also investigated the role of stereo-specificity of IP3 molecule and its analogs in binding with the IP3 receptor. Molecular docking simulations showed that the hydroxyl group at R6 position along with the phosphate group at R5 position in ‘R’ conformation is more favorable for IP3 interactions. Additionally, Arg-266 and Arg-510 showed π–π and hydrogen bond interactions and Ser-278 forms hydrogen bond interactions with the IP3 binding site. Thus, they are identified as crucial for the binding of antagonists.

Molecular Docking Studies of Indolyl-Benzodioxyl-Chalcone, Pyrrolyl-Benzodioxyl- Chalcone, and Thiophenyl-Benzodioxyl-Chalcone as an Antimalarial Agent

2021 ◽  
Vol 874 ◽  
pp. 136-142
Author(s):  
Kamilia Mustikasari ◽  
Joshua Eka Harap ◽  
Tanto Budi Susilo ◽  
Noer Komari
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Docking Studies ◽  
Kcal Mole ◽  
Docking Simulations ◽  
Drug Candidates ◽  
Hydrogen Bond Interactions ◽  
New Compounds ◽  
Native Ligand

The drug resistance condition of P. falciparum pose a major challenge in the fight against malaria. This prompts a comprehensive research in an effort to discover new drug candidates. Therefore, chalcone was modified into 24 new compounds, including indolyl-benzodioxyl-chalcone, pyrrolyl-benzodioxyl-chalcone, and thiophenyl-benzodioxyl-chalcone in the course of this study. Moreover, these compounds are commercial malaria mediciations screened for their inhibitory activity using molecular docking simulations. Subsequent results of combined indolyl-benzodioxyl-chalcone and PfDHFR-TS showed the intrinsic indolyl components produced stronger interactions referenced to pyrrolyl-benzodioxyl-chalcone, thiophenyl-benzodioxyl-chalcone, and chloroguanide. Under these circumstances, intense PfDHFR-TS-indolyl-benzodioxyl-chalcone complex was produced with lower binding affinity values (-7.32 to -8.43 kcal/mole) referenced to PfDHFR-TS-pyrrolyl-benzodioxyl-chalcone (-6.38 to -6.68 kcal/mole), PfDHFR-TS-Thiophenyl-benzodioxyl-chalcone (-6.47 to -6.52 kcal/mole), and PfDHFR-TS-chloroguanide (-6.75 kcal/mole). Furthermore, the hydrogen bond interactions developed by indolyl-benzodioxyl-chalcone (7-10) are observably similar to standard chloroguanide compounds and WR99210. These compounds also possess a binding affinity similar to WR99210 (native ligand) and are expected to be potentially anti-malarial candidates.

scholarly journals Receptor Tyrosine Kinases: Role in Cancer Progression

2006 ◽  
Vol 13 (5) ◽  
pp. 191-193
Author(s):  
V. Sangwan ◽  
M. Park
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Normal Tissue ◽  
Receptor Tyrosine Kinases ◽  
Tight Control ◽  
Tissue Patterning

Tight control of cell proliferation and morphogenesis in conjunction with programmed cell death (apoptosis) is required to ensure normal tissue patterning. [...]

scholarly journals ERK: A Double-Edged Sword in Cancer. ERK-Dependent Apoptosis as a Potential Therapeutic Strategy for Cancer

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2509
Author(s):  
Reiko Sugiura ◽  
Ryosuke Satoh ◽  
Teruaki Takasaki
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Tumor Cell Death ◽  
Cancer Treatments ◽  
Erk Activation ◽  
Cellular Processes ◽  
Dual Specificity ◽  
Anti Cancer ◽  
Dual Specificity Phosphatases

The RAF/MEK/ERK signaling pathway regulates diverse cellular processes as exemplified by cell proliferation, differentiation, motility, and survival. Activation of ERK1/2 generally promotes cell proliferation, and its deregulated activity is a hallmark of many cancers. Therefore, components and regulators of the ERK pathway are considered potential therapeutic targets for cancer, and inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic. Notably, ERK1/2 kinases also have pro-apoptotic functions under certain conditions and enhanced ERK1/2 signaling can cause tumor cell death. Although the repertoire of the compounds which mediate ERK activation and apoptosis is expanding, and various anti-cancer compounds induce ERK activation while exerting their anti-proliferative effects, the mechanisms underlying ERK1/2-mediated cell death are still vague. Recent studies highlight the importance of dual-specificity phosphatases (DUSPs) in determining the pro- versus anti-apoptotic function of ERK in cancer. In this review, we will summarize the recent major findings in understanding the role of ERK in apoptosis, focusing on the major compounds mediating ERK-dependent apoptosis. Studies that further define the molecular targets of these compounds relevant to cell death will be essential to harnessing these compounds for developing effective cancer treatments.

2-(4-Chlorophenyl)-N-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-3-methylbutanamide ethanol solvate

2006 ◽  
Vol 62 (5) ◽  
pp. o1836-o1838
Author(s):  
Jing-Li Cheng ◽  
Fang-Lin Wei ◽  
Wen-Jun Gui ◽  
Guo-Nian Zhu
Keyword(s):  
Hydrogen Bond ◽  
Title Compound ◽  
Cyano Group ◽  
Solvent Molecule ◽  
Hydroxyl Group ◽  
Asymmetric Unit ◽  
Hydrogen Bond Interactions ◽  
Compound C ◽  
Ethanol Solvate ◽  
Hydrogen Bonded

In the title compound, C22H16Cl3F3N4O·C2H6O, the asymmetric unit consists of one molecule of C22H16Cl3F3N4O and one ethanol solvent molecule which are connected through an N—H...O hydrogen bond. The H atom of the hydroxyl group of the solvent molecule is hydrogen bonded to the N atom of the cyano group. These hydrogen-bond interactions result in the formation of zigzag chains parallel to the a axis.

scholarly journals MOLECULAR DOCKING OF ANTITRYPANOSOMAL INHIBITORS FROM EUCALYPTUS TERETICORNIS FOR SLEEPING SICKNESS

2019 ◽  
pp. 191-195
Author(s):  
AARTHI RASHMI B ◽  
HARISHCHANDER A ◽  
PRIYANKA K ◽  
VASANTH NIRMAL BOSCO
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Binding Energy ◽  
Sleeping Sickness ◽  
Betulonic Acid ◽  
Eucalyptus Tereticornis ◽  
Hydrogen Bond Interaction ◽  
Hydrogen Bond Interactions ◽  
Bond Interaction ◽  
Pure Compounds

Objectives: This study aims to investigate the antitrypanosomal inhibitors of Eucalyptus tereticornis for sleeping sickness through molecular docking and studies on Absorption distribution metabolism excursion and toxicology (ADMET). Methods: In silico molecular docking in ArgusLab software and ADMET analysis in AdmetSAR software was performed for the antitrypanosomal inhibitors of E. tereticornis for sleeping sickness. Results: Interactions were studied for the ten proteins responsible for sleeping sickness with the 50 antitrypanosomal inhibitors of E. tereticornis. Docking was performed to see the interaction and the best binding energy of compounds with the proteins involved in sleeping sickness. The docking scores were highest for betulonic acid with −15.66 kcal/mol followed by euglobal with −12.24 kcal/mol, B-pinene with −10.313 kcal/mol, A-pinene with −10.3418 kcal/mol, and the least docking score for P-cymene with −10.6045 kcal/mol. Docking results showed that only betulonic acid and euglobal showed that hydrogen bond interaction was as b-pinene, a-pinene, and p-cymene yielded no hydrogen bond interactions so we will be taking the former docking results for further studies. The best docking result was shown by betulonic acid with trypanothione reductase giving binding energy of −15.66 kcal/mol with hydrogen bond interaction of 2.9, so this result was taken for further analysis. Conclusion: The results of the compound extracted from E. tereticornis will become physiological relevant only when (i) the pure compounds of this plant is available in large quantities; (ii) the Eucalyptus is biochemically stabilized to avoid degradation and enhance absorption in the gastrointestinal tract; and (iii) special delivery methods for this drug to reach the areas of treatment. In this work, the efficacy of E. tereticornis to act against trypanosomal protein was initiated and thus further research in this process would help us to take full advantage of the remedial effects of the compounds extracted from this plant.

scholarly journals Transcriptional alterations of protein coding and noncoding RNAs in triple negative breast cancer in response to DNA methyltransferases inhibition

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ramesh Elango ◽  
Radhakrishnan Vishnubalaji ◽  
Hibah Shaath ◽  
Nehad M. Alajez
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Dna Methylation ◽  
Cell Proliferation ◽  
Cell Death ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Dna Methyltransferases ◽  
Cellular Processes ◽  
Transcriptional Alterations

Abstract Background DNA methylation plays a crucial role in multiple cellular processes such as gene regulation, chromatin stability, and genetic imprinting. In mammals, DNA methylation is achieved by DNA methyltransferases (DNMTs). A number of studies have associated alterations in DNMT activity to tumorigenesis; however, the exact role of DNMTs in shaping the genome in triple negative breast cancer (TNBC) is still being unraveled. Methods In the current study, we employed two DNMT inhibitors (Decitabine and 5-Azacytidine), two TNBC models (MDA-MB-231 and BT-549) and whole transcriptome RNA-Seq and characterized the transcriptional alterations associated with DNMT inhibition. Colony forming unit (CFU), flow cytometry, and fluorescent microscopy were used to assess cell proliferation, cell cycle distribution, and cell death, respectively. Ingenuity pathway analysis (IPA) was used for network and pathway analyses. Results Remarkably, DNMT inhibition induced the expression of genes involved in endoplasmic reticulum response to stress, response to unfolder protein, as well as cobalamin metabolic processes. In contrast, suppression of cellular processes related to cell cycle and mitosis were hallmarks of DNMT inhibition. Concordantly, DNMT inhibition led to significant inhibition of TNBC cell proliferation, G2-M cell cycle arrest and induction of cell death. Mechanistically, DNMT inhibition activated TP53, NUPR1, and NFkB (complex) networks, while RARA, RABL6, ESR1, FOXM1, and ERBB2 networks were suppressed. Our data also identified the long noncoding RNA (lncRNA) transcriptional portrait associated with DNMT inhibition and identified 25 commonly upregulated and 60 commonly downregulated lncRNAs in response to Decitabine and 5-Azacytidinec treatment in both TNBC models. TPT1-AS1 was the most highly induced (6.3 FC), while MALAT1 was the most highly suppressed (− 7.0 FC) lncRNA in response to DNMT inhibition. Conclusions Taken together, our data provides a comprehensive view of transcriptome alterations in the coding and noncoding transcriptome in TNBC in response to DNMT inhibition.

scholarly journals Catalytic and Molecular Properties of Rabbit Liver Carboxylesterase Acting on 1,8-Cineole Derivatives

2012 ◽  
Vol 7 (9) ◽  
pp. 1934578X1200700
Author(s):  
María del H. Loandos ◽  
Ana C. Muro ◽  
Margarita B. Villecco ◽  
Marcelo F. Masman ◽  
Paul G.M. Luiten ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Molecular Modeling ◽  
Molecular Properties ◽  
Rabbit Liver ◽  
Enantioselective Hydrolysis ◽  
Docking Simulations ◽  
Hydrogen Bond Interactions ◽  
Molecular Dynamics Calculations ◽  
Hydrolysis Of

Rabbit liver carboxylesterase (rCE) was evaluated as the catalyst for the enantioselective hydrolysis of (±)-3-endo-acetyloxy-1,8-cineole [(±)-4], which yields (1S,3S,4R)-(+)-3-acetyloxy-1,8-cineole [(+)-4] and (1R,3R,4S)-(-)-3-hydroxy-1,8-cineole [(-)-3]. Enantioselective asymmetrization of meso-3,5-diacetoxy-1,8-cineol (5) gives (1S,3S,4R,5R)-(-)-3-acetyloxy-5-hydroxy-1,8-cineole (6), with high enantioselectivity. rCE has been chosen to perform both experiments and molecular modeling simulations. Docking simulations combined with molecular dynamics calculations were used to study rCE-catalyzed enantioselective hydrolysis of cineol derivatives. Both compounds were found to bind with their acetyl groups stabilized by hydrogen bond interactions between their oxygen atoms and Ser221.

scholarly journals Molecular docking analysis of stevioside with AKT and PPARγ

2021 ◽  
Vol 17 (1) ◽  
pp. 283-288
Author(s):  
Abilasha Deenadayalan ◽  
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Docking Studies ◽  
Autodock Vina ◽  
Docking Analysis ◽  
Hydrogen Bond Interactions ◽  
Ppar Γ ◽  
Molecular Docking Analysis

Stevioside is a diterpenoid glycoside consisting of an aglycone (steviol) and three glucose molecules. It is commonly used as an anti-hyperglycemic food because of its non-caloric property. Therefore, it is of interest to document the interactions of stevioside with AKT & PPAR-γ proteins using Autodock Vina PyRx docking techniques. Results of the docking studies indicate that stevioside had more than two hydrogen bond interactions with the AKT and PPAR γ protein for further consideration.

scholarly journals Molecular docking studies of 1, 3, 4 oxadiazoles Derivatives as anti-convulsive agents

2020 ◽  
Vol 8 (1) ◽  
pp. 151-179
Author(s):  
Sachin Jangra ◽  
Sachin Kumar ◽  
Manjusha Choudhary
Keyword(s):  
Amino Acids ◽  
Hydrogen Bond ◽  
Molecular Docking ◽  
Binding Site ◽  
Gabaa Receptor ◽  
Small Molecule ◽  
Future Research ◽  
Computational Technique ◽  
Standard Drug ◽  
Hydrogen Bond Interactions

Molecular docking is a computational technique that places a small molecule (ligand) in the binding site of its macromolecular target (receptor) and estimates its binding affinity. The present study attempted the high throughput in-silico screening of 65 compounds docked with the GABAA receptor (PDB ID: 4COF) using Molegro virtual docker (6.0). Out of these 65 compounds, 17 compounds showed very good mol dock score in ranging between -66.344 & -102.653. Ethosuximide and Carbamazepine drugs was used as a standard drug which showed mol dock score -50.6357 & -58.5047 respectively. Most of test compounds demonstrated excellent number of hydrogen bond interactions viz compounds 33, 38, 39, 45, 47, 53, 54, 59, 61, 62, 63, 64 & 65 which showed 7 to 11 number of hydrogen bond interactions as compared to standard drug interactions values 6 & 5 respectively and also showed the interaction with same amino acids Glu52, Ser51and Val53 and some other amino acids Asn54, Thr58 and Thr133 also showed very acceptable bond length less than 3.91Å. The obtained results indicated that all studied ligands have similar position and orientation inside the putative binding site of GABAA receptor (PDB ID: 4COF) which reveals a large space bounded by a membrane-binding domain which serves as an entry channel for substrate to the active site. In addition, the affinity of any small molecule can be considered as a unique tool in the field of drug design and offer prospective in future research to develop a potent anticonvulsant agent.

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