Figure 2 - uploaded by Kiran Bharat Lokhande
Content may be subject to copyright.
Leucine-rich repeats present in the cyclin E receptor (PDB ID: 2AST), that forms alpha/beta horseshoe fold.
Source publication
Deguelin is a major active ingredient and principal component in several plants and it is a potential molecule to target proteins of cancer cell signaling pathway. As a complex natural extract, deguelin interacts with various molecular targets to exert its anti-tumor properties at nanomolar level. It induces cell apoptosis by blocking anti-apoptoti...
Contexts in source publication
Context 1
... E [PDB ID: 2AST (Resolution: 2.30A ° )], has motif called Leucine-rich repeats (LRR). These repeats responsible for formation of beta-alpha structural units (Fig. 2) fold in horseshoe (or arc) shape on the concave face. LRR are involved in protein-protein interaction as domain exposed to the solvent 25,26 . Two residues from inhibitory site present in this LRR domain including Phe2169 and Val2192. structural analysis. PROMOTIF 27 program provides information about secondary structure of given pro- ...
Context 2
... to probe the flexibility of the deguelin and both receptors complexes, the root mean square fluctuation (RMSF) for C-alpha atoms of all the residues are compared with duration of 100 ns MD simulations. It is notable that, the RMSF trajectories of cyclin D1 (Supplementary Fig. 1) is suggesting sta- bility of the complexes with a related more rigid and stable conformations than cyclin E ( Supplementary Fig. 2). The analysis reveals that, hydrogen atom of protonated −NH3+ group of Lys35 from 2W96 binds to oxygen atom from electron donating methoxy group of deguelin at 2nd position ( Fig. 6(a changed in dynamically stable conformation due to orientation of deguelin during simulation and oxygen atom at 3rd position of deguelin interacted with protonated −NH3+ group of Lys35 ( Fig. 6(b)). ...
Similar publications
Post-translational modifications are known to be widely involved in the regulation of various biological processes, through the extensive diversification of each protein function at the cellular network level. In order to unveil the system-wide function of the protein lysine modification in cancer cell signaling, we performed global acetylation and...
Citations
... 93,94 In contrast, deguelin has been reported to selectively inhibit the growth of cancer cells by targeting oncogenic functions including cell cycle, apoptosis, and angiogenesis. 48,54,[95][96][97] For instance, it has been reported that treatment with deguelin induces apoptosis in lung cancer cells by downregulating AKT phosphorylation and stimulating ROS. 98 Li et al demonstrated that deguelin inhibits cell growth in NSCLC by downregulating hexokinase 2, a key player in glycolysis metabolism. ...
Background
Ovarian cancer is one of women’s malignancies with the highest mortality among gynecological cancers. Paclitaxel is used in first-line ovarian cancer chemotherapy. Research on paclitaxel-resistant ovarian cancer holds significant clinical importance.
Methods
Cell viability and flow cytometric assays were conducted at different time and concentration points of deguelin and paclitaxel treatment. Immunoblotting was performed to assess the activation status of key signaling molecules important for cell survival and proliferation following treatment with deguelin and paclitaxel. The fluo-3 acetoxymethyl assay for P-glycoprotein transport activity assay and cell viability assay in the presence of N-acetyl-L-cysteine were also conducted.
Results
Cell viability and flow cytometric assays demonstrated that deguelin resensitized paclitaxel in a dose- and time-dependent manner. Cotreatment with deguelin and paclitaxel inhibited EGFR and its downstream signaling molecules, including AKT, ERK, STAT3, and p38 MAPK, in SKOV3-TR cells. Interestingly, cotreatment with deguelin and paclitaxel suppressed the expression level of EGFR via the lysosomal degradation pathway. Cotreatment did not affect the expression and function of P-glycoprotein. N-acetyl-L-cysteine failed to restore cell cytotoxicity when used in combination with deguelin and paclitaxel in SKOV3-TR cells. The expression of BCL-2, MCL-1, and the phosphorylation of the S155 residue of BAD were downregulated. Moreover, inhibition of paclitaxel resistance by deguelin was also observed in HeyA8-MDR cells.
Conclusion
Our research showed that deguelin effectively suppresses paclitaxel resistance in SKOV3-TR ovarian cancer cells by downregulating the EGFR and its downstream signaling pathway and modulating the BCL-2 family proteins. Furthermore, deguelin exhibits inhibitory effects on paclitaxel resistance in HeyA8-MDR ovarian cancer cells, suggesting a potential mechanism for paclitaxel resensitization that may not be cell-specific. These findings suggest that deguelin holds promise as an anticancer therapeutic agent for overcoming chemoresistance in ovarian cancer.
... OPLS-2005 force field was utilized for the MD simulations. Trajectory analysis was performed using the 'Simulation Event Analysis' module of Schrodinger's Maestro to calculate root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and intermolecular hydrogen bonds (Lokhande et al. 2021(Lokhande et al. , 2019. ...
Aurora Kinase B belongs to the serine kinase family. It plays an essential role in cell division and participates in mitosis and chromatid segregation. Overexpression, polymorphism, and splicing variants in the protein lead to tumorigenesis, leading to cancer. Flavones belong to the class of flavonoids and are derived from plants and show anti-cancer activities. Fluoro flavones and their analogs are taken from the PubChem database, resulting in 3882 compounds which is 90% similar to the fluoro flavones. Lipinski's rule of five, REOS and PAINS drug-like filters were applied which resulted 2448 compounds. These compounds are docked with Aurora Kinase B using SP and XP modules of Glide software. The best binding scores for SP docking were − 9.153 kcal/mol for the compound with CID: 44298667, and XP docking was − 10.287 kcal/mol with CID: 101664315. Enrichment calculations were done using Aurora Kinase B's decoys to validate the docking result. The resulting R² = 0.96 from enrichment calculations suggests that the docking protocol is valid. The SP and XP docking lead compounds and the Fluoro flavone were subjected to 100 ns MD simulation to probe the protein–ligand complex stability. Also, the binding free energies between the Aurora kinase B and lead compounds were computed by Prime MM/GBSA module. The result suggests that the lead compounds bind more strongly with Aurora Kinase B than the Fluoro flavone. These lead compounds can be further evaluated in vitro and in vivo and can be used as future novel drugs for the curation of cancer.
Graphical abstract
... Recognizing the uniqueness of their possibilities to treat a variety of diseases, we looked at a subset of its derivatives in this article to learn more about how they function as inhibitors against the above-mentioned viral non-structural proteins using in silico approaches [21][22][23]. Recent studies on the SARS-CoV-2 targets, such as Mpro, PLpro and RdRP, have highlighted the value of structure-based drug design in the search for powerful compounds from a variety of chemical libraries, including azadirachtins, ceramicines, withanolides and nucleotide analog medicines [24][25][26][27]. ...
Introduction:
Coronavirus disease 2019 (COVID-19) is an unprecedented pandemic, threatening human health worldwide. The need to produce novel small-molecule inhibitors against the ongoing pandemic has resulted in the use of drugs such as chloroquine, azithromycin, dexamethasone, favipiravir, ribavirin, remdesivir and azithromycin. Moreover, the reports of the clinical trials of these drugs proved to produce detrimental effects on patients with side effects like nephrotoxicity, retinopathy, cardiotoxicity and cardiomyopathy. Recognizing the need for effective and non-harmful therapeutic candidates to combat COVID-19, we aimed to develop promising drugs against SARS-COV-2.
Discussion:
In the current investigation, high-throughput virtual screening was performed using the Comprehensive Marine Natural Products Database against five non-structural proteins: Nsp3, Nsp5, Nsp12, Nsp13 and Nsp15. Furthermore, standard precision (SP) docking, extra precision (XP) docking, binding free energy calculation and absorption, distribution, metabolism, excretion and toxicity studies were performed using the Schrӧdinger suite. The top-ranked 5 hits obtained by computational studies exhibited to possess a greater binding affinity with the selected non-structural proteins. Amongst the five hits, CMNPD5804, CMNPD20924 and CMNPD1598 hits were utilized to design a novel molecule (D) that has the capability of interacting with all the key residues in the pocket of the selected non-structural proteins. Furthermore, 200 ns of molecular dynamics simulation studies provided insight into the binding modes of D within the catalytic pocket of selected proteins.
Conclusion:
Hence, it is concluded that compound D could be a promising inhibitor against these non-structural proteins. Nevertheless, there is still a need to conduct in vitro and in vivo studies to support our findings.
... Even in Indium-silico investigation, a metal-nanocomposite structure with the antiviral medicine ribavirin using 12 metals was devised using Avogadro software. This structure was then subjected to energy minimization [9]. Additionally, research facilities have examined a growing number of metal-based medications for their antiviral activity using Avogadro software. ...
This research focuses on obtaining the behavior of chemical compounds with respect to their molecular weight and optimization energy based on the variation in properties in organic carbon links. Here, behavioral analysis of compounds is used in the application of a metal organic framework to denote the high-grade compounds. The grade was selected based on the essential measure of optimization energy and molecular weight, and in turn, depicts the stability of material. Computation of the optimization energy and molecular weight of chemical compounds was performed with Avogadro software. Several force fields can be considered to compute optimized energy. Exclusively, three force fields, namely, the Universal Force Field (UFF), the General Amber Force Field (GAFF), and the Ghemical force field (Ghemical) were selected from Avogadro as these were more relevant to compounds considered in this research. The various chemical compounds examined in this work are Aluminum (Al), Boron (Br), Calcium (Ca), Chlorine (Cl), Indium (In), Potassium (K), Scandium (Sc), Silicon (Si), and Tungsten (W). Hence, molecular modeling of different compounds incorporated with three different force fields was evaluated in this work. In this study, we found that the In structure has more energy reduction, of 22.673 kJ mol−1 in UFF, when compared with the other two force fields. Thus, In has higher potential with more stability.
... The 10 ns molecular dynamics (MD) simulations for the complexes of tetracosanedioic acid (PubChem CID2724554) and the positive control, trichostatin A (PubChem CID: 444732) with histone deacetylase, were performed with the help of Desmond software to confirm the binding stability and strength of the complex [45]. Desmond has inbuilt functions to add pressure, system volume, and temperature, as well as many functionalities to accomplish protein-ligand binding. ...
... At the same time, observations of viability and cell death in these two types of breast cancer cells are distinct. These data can be explained and linked with their caspase 3-deficient MCF-7 cells relative to caspase 3-active ZR-51-1 breast cancer cells [45][46][47]. Despite similar WT p53 profiles in MCF-7 and ZR-75-1 breast cancer cells, the status of caspase 3 is distinct. ...
... Among various FFAs, erucic and stearic acids are suggested for antitumor effects in nature. Conversely, linoleic acids, oleic acid, and palmitic acid are indicated for protumor effects [10][11][12][16][17][18][19][20][21][22]40,41,[43][44][45]. Studies suggest that distinctive positions of double bonds and additional functional groups such as hydroxyl groups and carboxyl groups in unsaturated fatty acids obstruct conversion into prostaglandins, which are wellknown agents in inflammation and cancer proliferation [40,41,[43][44][45]. ...
Objective:
The objective of this study was to explore the biological relevance of free fatty acids derived from cow urine DMSO fraction (CUDF) by employing in vitro and in silico approaches.
Background:
Metabolic heterogeneity at the intra- and intercellular levels contributes to the metabolic plasticity of cancer cells during drug-induced response. Free fatty acid (FFA) availability at intra- and intercellular levels is related to tumor heterogeneity at interpatient and xeno-heterogeneity levels.
Methods:
We collected fresh urine from healthy cows and subjected it to fractionation in DMSO using drying, vortexing, and centrifugation. Finally, the sterile filtrate of cow urine DMSO fraction (CUDF) was evaluated for antiproliferative and proapoptotic effects in MCF-7 and ZR-75-1 breast cancer cells using routine cell-based assays. Intracellular metabolites were studied with the help of a novel in-house vertical tube gel electrophoresis (VTGE) method to reveal the nature of CUDF components in MCF-7 cells. Identified intracellular FFAs were studied for their molecular interactions with targeted receptor histone deacetylase (HDAC) using molecular docking and molecular dynamics (MD) simulations.
Results:
CUDF showed a significant reduction in cell viability and cell death in MCF-7 and ZR-75-1 breast cancer cells. Interestingly, FFAs tetracosanedioic acid, 13Z-docosenoic acid (erucic acid), nervonic acid, 3-hydroxy-tetradecanoic acid, and 3-hydroxcapric acid were found inside the treated MCF-7 cancer cells. These FFAs, including tetracosanedioic acid, indicated a specific affinity to HDAC at their inhibitory sites, similar to trichostatin A, a known inhibitor.
Conclusions:
This study reports on FFAs derived from CUDF as potential antiproliferative and pro-cell death agents against breast cancer cells. MD simulations hinted at tetracosanedioic acid and other FFAs as inhibitors of HDAC that could explain the observed effects of FFAs in cancer cells.
... FR180204 is a selective target of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2) pathway in the Mitogen-activated protein kinase (MAPK). It inhibits ERK through competition with ATP (Type I ATP inhibitor) [38,39]. FR180204 has been shown to have an antiproliferative effect in different cancer cell lines, including adrenocortical, mesothelioma, prostate, pancreatic, and colorectal cell lines [40,41]. ...
... A molecular dynamics simulation was deployed to provide insights about the interaction, stability of two hit compounds and the control drug inside HSP27, and conformational derivations of these compounds or HSP27 that may occur inside the biological system in various conditions with respect to time [38]. From this present study, the two hit compounds showed attributes that are in line with stability cum affinity to HSP27 (Figures 5 and 6). ...
... The energy minimization was done using the steepest descent method throughout the 100 ns MD simulation with EF = a n ∕ A N an OPLS_2005 force field [44,45]. For the initial 400 ps, all the systems were heated linearly at NVT (N = number of atoms, V = volume, T = temperature) ensemble from 0 to 300 K temperature. ...
The overexpression of cyclin D1 and cyclin E due to their oncogenic potential and amplification has been associated with a higher mortality rate in many cancers. The deguelin is a natural compound, has shown promising anti-cancer activity by directly binding cyclin D1 and cyclin E and thus suppressing its function. The C7a atomic position of deguelin structure contains a proton that generates stabilized radical, as a result, decomposed deguelin reduces its structural stability and significantly decreases its biological activity. To design deguelin derivatives with the reduced potential side effect, series of B, C-ring truncated derivatives were investigated as cyclin D1 and cyclin E inhibitors. R-group-based enumeration was implemented in the deguelin scaffold using the R-group enumeration module of Schrödinger. Drug-Like filters like, REOS and PAINs series were applied to the enumerated compound library to remove compounds containing reactive functional groups. Further, screened compounds were docked within the ligand-binding cavity of cyclin D1 and cyclin E crystal structure, using Glide SP and XP protocol to obtain docking poses. Enrichment calculations were done using SchrÖdinger software, with 1000 decoy compounds (from DUD.E database) and 60 compounds (XP best poses) along with deguelin, to validate the docking protocol. The receiver operating characteristic (ROC) curve indicates R² = 0.94 for cyclin D1 and R² = 0.79 for cyclin E, suggesting that the docking protocol is valid. Besides, we explored molecular dynamics simulation to probe the binding stability of deguelin and its derivatives within the binding cavity of cyclin D1 and cyclin E structures which are associated with the cyclin D1 and cyclin E inhibitory mechanism.
Graphic abstract
... A molecular modeling study was undertaken using the Molecular Operating Environment (MOE) [61], a drug discovery software platform that integrates visualization, modeling and simulations, as well as methodology development, into one package. Molecular modeling studies were performed using Molecular Operating Environment (MOE, 2019) software on Dell Core i7 processor with 1.9 GH, 16 GB memory, and a Windows 10, 64-bit operating system. ...
Multiple biological functions of Mentha pulegium extract were evaluated in the current work. Phytochemical components of the M. pulegium extract were detected by Gas Chromatography-Mass Spectrometry (GC-MS) and High-performance liquid chromatography (HPLC). Moreover, M. pulegium extract was estimated for antioxidant potential by 2,2-Diphenyl-1-picryl-hydrazyl-hydrate (DPPH) free radical scavenging, antimicrobial activity by well diffusion, and anticoagulant activity via prothrombin time (PT) and activated partial thromboplastin time (APTT). GC-MS analysis detected compounds including cholesterol margarate, stigmast-5-en-3-ol, 19-nor-4-androstenediol, androstan-17-one, pulegone-1,2-epoxide, isochiapin B, dotriacontane, hexadecanoic acid and neophytadiene. Chrysoeriol (15.36 µg/mL) was followed by kaempferol (11.14 µg/mL) and 7-OH flavone (10.14 µg/mL), catechin (4.11 µg/mL), hisperdin (3.05 µg/mL), and luteolin (2.36 µg/mL) were detected by HPLC as flavonoids, in addition to ferulic (13.19 µg/mL), cinnamic (12.69 µg/mL), caffeic (11.45 µg/mL), pyrogallol (9.36 µg/mL), p-coumaric (5.06 µg/mL) and salicylic (4.17 µg/mL) as phenolics. Antioxidant activity was detected with IC50 18 µg/mL, hemolysis inhibition was recorded as 79.8% at 1000 μg/mL, and PT and APTT were at 21.5 s and 49.5 s, respectively, at 50 μg/mL of M. pulegium extract. The acute toxicity of M. pulegium extract was recorded against PC3 (IC50 97.99 µg/mL) and MCF7 (IC50 80.21 µg/mL). Antimicrobial activity of M. pulegium extract was documented against Bacillus subtilis, Escherichia coli, Pseudomonasaureus, Candida albicans, Pseudomonas aeruginosa, but not against black fungus Mucor circinelloides. Molecular docking was applied using MOE (Molecular Operating Environment) to explain the biological activity of neophytadiene, luteolin, chrysoeriol and kaempferol. These compounds could be suitable for the development of novel pharmacological agents for treatment of cancer and bacterial infections.
... Before molecular docking, the ligand and receptor were prepared using AutoDockTools-1.5.7, which mainly involved removing water molecules from the receptor, adding hydrogen atoms, and generating coordinate files. At the same time, the ligands were detected root, chose torsions, and generated coordinate files [36,37]. Then, we generated the grid box based on the receptor active site, and the size and coordinates of the grid box are as follows. ...
Background
Patients with lung adenocarcinoma (LUAD) may be more predisposed to coronavirus disease 2019 (COVID-19) and have a poorer prognosis. Currently, there is still a lack of effective anti-LUAD/COVID-19 drugs. Thus, this study aimed to screen for an effective anti-LUAD/COVID-19 drug and explore the potential mechanisms.
Methods
Firstly, we performed differentially expressed gene (DEG) analysis on LUAD transcriptome profiling data in The Cancer Genome Atlas (TCGA), where intersections with COVID-19-related genes were screened out. Then, we conducted Cox proportional hazards analyses on these LUAD/COVID-19 DEGs to construct a risk score. Next, LUAD/COVID-19 DEGs were uploaded on Connectivity Map to obtain drugs for anti-LUAD/COVID-19. Finally, we used network pharmacology, molecular docking, and molecular dynamics (MD) simulation to explore the drug’s therapeutic targets and potential mechanisms for anti-LUAD/COVID-19.
Results
We identified 230 LUAD/COVID-19 DEGs and constructed a risk score containing 7 genes (BTK, CCL20, FURIN, LDHA, TRPA1, ZIC5, and SDK1) that could classify LUAD patients into two risk groups. Then, we screened emetine as an effective drug for anti-LUAD/COVID-19. Network pharmacology analyses identified 6 potential targets (IL6, DPP4, MIF, PRF1, SERPING1, and SLC6A4) for emetine in anti-LUAD/COVID-19. Molecular docking and MD simulation analyses showed that emetine exhibited excellent binding capacities to DDP4 and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Conclusions
This study found that emetine may inhibit the entry and replication of SARS-CoV-2 and enhance tumor immunity by bounding to DDP4 and Mpro.
... Importantly, deguelin can enhance the sensitivity of tumor cells to chemotherapy drugs and radiotherapy and has no obvious toxicity and inhibitory effect on the growth of normal cells [6]. The main antitumor effects of deguelin include inhibiting the proliferation, invasion, and metastasis of tumor cells; promoting the apoptosis of tumor cells; delaying the tumor cell cycle; and inducing DNA damage of tumor cells [8][9][10][11][12][13]. However, the molecular mechanisms of deguelin in antitumor effects remain completely unclear, a situation that needs to be explored in the future. ...
Non-small-cell lung cancer (NSCLC) is the most common lung cancer and a major cause of cancer mortality worldwide. Deguelin plays a vital inhibitory role in NSCLC initiation and development. However, the downstream mechanism of deguelin-suppressed metastasis of NSCLC cells is still not completely understood. Interestingly, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and Krüppel-like factor 4 (KLF4) also contribute to inhibition of metastasis in NSCLC cells. Here, we demonstrated that deguelin significantly upregulated PTEN and KLF4 expressions and PTEN positively upregulated KLF4 expression in NSCLC cells including A549 and PC9 cells. Moreover, overexpressions of PTEN and KLF4 inhibited the migration and invasion of NSCLC cells, an effect similar to that of deguelin. Furthermore, overexpressions of PTEN and KLF4 could suppress the epithelial-mesenchymal transition (EMT), an effect also similar to that of deguelin. Additionally, deguelin displayed a significant antitumor ability by upregulating PTEN and KLF4 expressions in mice model with NSCLC cells. Together, these results indicated that deguelin could be a potential therapeutic agent through upregulating PTEN and KLF4 expressions for NSCLC therapy.
