scholarly journals Investigation of Molecular Modeling And Molecular Dynamics Simulation In BRCA-1 And BRCA-2 Genes of Amygdalin Ligand

2021 ◽  
Author(s):  
Erkan ÖNER ◽  
Ilter demirhan ◽  
Arabinda GHOSH ◽  
Meltem GUNGOR ◽  
Ali Erdinc YALIN ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
Md Simulation ◽  
Hydrophobic Interactions ◽  
Dynamics Simulation ◽  
Cancer Drug ◽  
Active Inhibitor ◽  
Brca 1 ◽  
Brca 2

Abstract Breast cancer is the most common type of cancer and the most fatal type among women. BRCA-1 and BRCA-2 are tumor suppressor genes known to cause breast cancer. Drug studies have become very important to target the production of more accurate drugs by reducing the cost with the previous designs of drugs in this field. Amygdalin is used in the treatment of especially cancer, characterized by the loss of red blood cell production. In this study, which was conducted for the first time, it was aimed to examine the use of amygdalin in breast cancer treatment by coupling to the active regions of BRCA-1 and BRCA-2 genes by molecular docking method. The best attachment scores were selected. Amygdalin was taken from PubChem database in sdf format. According to the molecular insertion results, the free energy of the amygdalin ligand for binding to the BRCA-1 protein was -4.8 kcal/mol and the free energy for binding to the BRCA-2 protein was -7.2 kcal/mol also include Ki values. MD simulation was performed using Desmond. Insertion results show that the amygdalin ligand binds more strongly to the BRCA-2 protein than to the BRCA-1 protein. MD simulation for the highly active inhibitor Amigydalin in complex with protein BRCA-2 revealed that the stabilization of ligand was achieved due to the formation of uninterrupted hydrophobic interactions. Due to the binding power of amygdalin ligand, it reveals a unique structure for breast cancer and it is thought to be a reference for designing new molecules with the same structure against cancer and applying these molecules in vivo and in vitro studies.

Polymer Coated Iron Nanoparticles: Radiolabeling & In Vitro Studies

2020 ◽  
Vol 13 ◽  
Author(s):  
Selin Yılmaz ◽  
Çiğdem İçhedef ◽  
Kadriye Buşra Karatay ◽  
Serap Teksöz
Keyword(s):  
Breast Cancer ◽  
Drug Delivery ◽  
Iron Oxide ◽  
Cancer Cells ◽  
Iron Oxide Nanoparticles ◽  
Breast Cancer Cells ◽  
Cancer Drug ◽  
Oxide Nanoparticles ◽  
Sem Images

Backgorund: Superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively used for targeted drug delivery systems due to their unique magnetic properties. Objective: In this study, it’s aimed to develop a novel targeted 99mTc radiolabeled polymeric drug delivery system for Gemcitabine (GEM). Methods: Gemcitabine, an anticancer agent, was encapsulated into polymer nanoparticles (PLGA) together with iron oxide nanoparticles via double emulsion technique and then labeled with 99mTc. SPIONs were synthesized by reduction–coprecipitation method and encapsulated with oleic acid for surface modification. Size distribution and the morphology of the synthesized nanoparticles were caharacterized by dynamic light scattering(DLS)and scanning electron microscopy(SEM), respectively. Radiolabeling yield of SPION-PLGAGEM nanoparticles were determined via Thin Layer Radio Chromatography (TLRC). Cytotoxicity of GEM loaded SPION-PLGA were investigated on MDA-MB-231 and MCF7 breast cancer cells in vitro. Results: SEM images displayed that the average size of the drug-free nanoparticles was 40 nm and the size of the drug-loaded nanoparticles was 50 nm. The diameter of nanoparticles were determined as 366.6 nm by DLS, while zeta potential was found as-29 mV. SPION was successfully coated with PLGA, which was confirmed by FTIR. GEM encapsulation efficiency of SPION-PLGA was calculated as 4±0.16 % by means of HPLC. Radiolabeling yield of SPION-PLGA-GEM nanoparticles were determined as 97.8±1.75 % via TLRC. Cytotoxicity of GEM loaded SPION-PLGA were investigated on MDA-MB-231 and MCF7 breast cancer cells. SPION-PLGA-GEM showed high uptake on MCF-7, whilst incorporation rate was increased for both cell lines which external magnetic field application. Conclusion: 99mTc labeled SPION-PLGA nanoparticles loaded with GEM may overcome some of the obstacles in anti-cancer drug delivery because of their appropriate size, non-toxic, and supermagnetic characteristics.

Prevascularized, Co-Culture Model for Breast Cancer Drug Development

2012 ◽  
Author(s):  
Lauren Marshall ◽  
Isabel Löwstedt ◽  
Paul Gatenholm ◽  
Joel Berry
Keyword(s):  
Breast Cancer ◽  
Drug Development ◽  
Three Dimensional ◽  
Human Tumor ◽  
3D Models ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Anti Cancer

The objective of this study was to create 3D engineered tissue models to accelerate identification of safe and efficacious breast cancer drug therapies. It is expected that this platform will dramatically reduce the time and costs associated with development and regulatory approval of anti-cancer therapies, currently a multi-billion dollar endeavor [1]. Existing two-dimensional (2D) in vitro and in vivo animal studies required for identification of effective cancer therapies account for much of the high costs of anti-cancer medications and health insurance premiums borne by patients, many of whom cannot afford it. An emerging paradigm in pharmaceutical drug development is the use of three-dimensional (3D) cell/biomaterial models that will accurately screen novel therapeutic compounds, repurpose existing compounds and terminate ineffective ones. In particular, identification of effective chemotherapies for breast cancer are anticipated to occur more quickly in 3D in vitro models than 2D in vitro environments and in vivo animal models, neither of which accurately mimic natural human tumor environments [2]. Moreover, these 3D models can be multi-cellular and designed with extracellular matrix (ECM) function and mechanical properties similar to that of natural in vivo cancer environments [3].

scholarly journals Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): an in silico analysis to identify novel drug candidates to combat COVID-19 pandemic

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Ghazala Muteeb ◽  
Adil Alshoaibi ◽  
Mohammad Aatif ◽  
Md. Tabish Rehman ◽  
M. Zuhaib Qayyum
Keyword(s):  
Hydrophobic Interactions ◽  
In Silico Analysis ◽  
Salt Bridge ◽  
Competitive Inhibitor ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Energy Calculation

AbstractThe recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score <  − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski’s, Veber’s, PAINS and Brenk’s filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies.

scholarly journals Breast Cancer Cells in Microgravity: New Aspects for Cancer Research

2020 ◽  
Vol 21 (19) ◽  
pp. 7345 ◽  
Author(s):  
Mohamed Zakaria Nassef ◽  
Daniela Melnik ◽  
Sascha Kopp ◽  
Jayashree Sahana ◽  
Manfred Infanger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Breast Cancer Cells ◽  
De Novo ◽  
Tumor Model ◽  
Cancer Drug ◽  
Cancer Therapies

Breast cancer is the leading cause of cancer death in females. The incidence has risen dramatically during recent decades. Dismissed as an “unsolved problem of the last century”, breast cancer still represents a health burden with no effective solution identified so far. Microgravity (µg) research might be an unusual method to combat the disease, but cancer biologists decided to harness the power of µg as an exceptional method to increase efficacy and precision of future breast cancer therapies. Numerous studies have indicated that µg has a great impact on cancer cells; by influencing proliferation, survival, and migration, it shifts breast cancer cells toward a less aggressive phenotype. In addition, through the de novo generation of tumor spheroids, µg research provides a reliable in vitro 3D tumor model for preclinical cancer drug development and to study various processes of cancer progression. In summary, µg has become an important tool in understanding and influencing breast cancer biology.

In-silico Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Novel Isoxazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer

2019 ◽  
Vol 11 (2) ◽  
pp. 118-128 ◽  
Author(s):  
Rajagopal Kalirajan ◽  
Arumugasamy Pandiselvi ◽  
Byran Gowramma ◽  
Pandiyan Balachandran
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
In Silico ◽  
Therapeutic Potential ◽  
Binding Free Energy ◽  
Breast Cancers ◽  
Molecular Docking Study ◽  
In Silico Admet

Background: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. Objective: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. Methods: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. Results: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. Conclusion: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.

scholarly journals Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach

2021 ◽  
Vol 11 ◽  
Author(s):  
Prem Prakash Kushwaha ◽  
Atul Kumar Singh ◽  
Tanya Bansal ◽  
Akansha Yadav ◽  
Kumari Sunita Prajapati ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Active Site ◽  
Md Simulation ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Kcal Mole ◽  
Hydrogen Bond Formation ◽  
Docking Score

The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro targets with a docking score of -8.22, -6.86, and -9.73 kcal/mole, respectively. Further, MS 3, 7-Hydroxyaloin B, 10-Hydroxyaloin A, showed -9.57, -7.07, -8.57 kcal/mole docking score against Spike, RdRP, and Mpro targets respectively. The MD simulation was performed to study the favorable confirmation and energetically stable complex formation ability of Isoquercetin and 10-Hydroxyaloin A phytochemicals in Mpro-unbound/ligand bound/standard inhibitor bound system. The parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape, principal component analysis showed that the lead phytochemicals form stable and energetically stabilized complex with the target protein. Further, MM-PBSA analysis was performed to compare the Gibbs free energy of the Mpro-ligand bound and standard inhibitor bound complexes. The analysis revealed that the His-41, Cys145, Met49, and Leu27 amino acid residues were majorly responsible for the lower free energy of the complex. Drug likeness and physiochemical properties of the test compounds showed satisfactory results. Taken together, the study concludes that that the Isoquercetin and 10-Hydroxyaloin A phytochemical possess significant efficacy to bind SARS-Cov-2 Mpro active site. The study necessitates further in vitro and in vivo experimental validation of these lead phytochemicals to assess their anti-SARS-CoV-2 potential.

scholarly journals Breast Cancer Drug Approvals Issued by EMA: A Review of Clinical Trials

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5198
Author(s):  
Simona Duranti ◽  
Alessandra Fabi ◽  
Marco Filetti ◽  
Rosa Falcone ◽  
Pasquale Lombardi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Clinical Benefit ◽  
Triple Negative ◽  
Locally Advanced ◽  
Cancer Drug ◽  
European Medicines Agency ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Brca 1

Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for the treatment of breast cancer approved by European Medicines Agency between January 2015 and June 2021. In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications.

BRCA 1 and BRCA 2 mutations in Saudi breast cancer patients (single institution).

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 10-10 ◽  
Author(s):  
Omalkhair A. M. Abulkhair
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Bilateral Breast Cancer ◽  
Cultural Practice ◽  
Reproductive Pattern ◽  
Saudi Women ◽  
Brca 1 ◽  
Brca 2

10 Background: Breast cancer is the commonest malignancy among Saudi females accounting for 25% of all female cancers with a median age at diagnosis of 47 years (1,2). In Saudi, breast cancer showed an increased incidence attributed to many factors such as different lifestyles, reproductive pattern, family history, which was reported to account for 59%, dietary or cultural practice of Saudi women (2,3,4,5). The multifunctional and highly penetrant BRCA 1 and BRCA 2 are the two major breast cancer pre-disposition genes, accounting for about 20% of breast cancer families (6,7). To our knowledge, the prevalence of BRCA 1 and BRCA 2 mutations in native Saudi population is sparse (8,9). Our aim is to describe the findings of BRCA mutation testing in native Saudi patients with breast cancer in a large Ministry of National Guard Health Affairs (NGHA) community-based teaching hospital. Methods: In this study, 75 out of 516 patients with breast cancer who were clinically and histopathologically diagnosed at NGHA from October 2010 to April 2014 were included. Selection criteria: aged ≤ 40 years bilateral breast cancer, triple-negative breast cancer, strongly first degree family history at young age and male breast cancer. Molecular alterations were performed by direct gene sequencing, multiple ligation – dependent probe amplification (MLPA) at Bioscentia human genetic testing in Germany. Results: 75 native Saudi were enrolled and test performed for them. 18 patients (24%) were found to have mutation of which 10 in BRCA One and six in BRCA 2. Two have both BRCA 1 and BRCA 2. Seven patients have the same with deleterious mutations in BRCA 1 gene. Two of them are mother and daughter and other five are unrelated. The mean age of breast cancer diagnosis in the mutation carriers was 38 years. Triple negative breast cancer (TNBC) diagnosed in six patients, bilateral breast cancer diagnosed in one, first-degree family history in eight and second degree in 10 patients and four with no family history. Conclusions: BRCA 1 and BRCA 2 mutations are an important contributor to the etiology of breast cancer in Saudi women. A mutation in BRCA 1, C 1648 > C p, Asn550His in exon 10 has been reported as disease causing (11) and it is found in our study in seven patients. Such mutation might be specific for Saudi, so further studies are highly recommended.

Antitumor activity of trabectedin and lurbinectedin in germline BRCA2 carriers with metastatic breast cancer (MBC) as compared to BRCA1 carriers: Analysis of two phase II trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 574-574
Author(s):  
Judith Balmana Gelpi ◽  
Jan Antoni Lubinski ◽  
Banu Arun ◽  
Tomasz Byrski ◽  
Melinda L. Telli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Single Agent ◽  
Metastatic Breast ◽  
Cross Resistance ◽  
Hematological Toxicity ◽  
Phase Ii Trials ◽  
Brca 1 ◽  
Brca 2 ◽  
Grade 3

574 Background: BRCA 1/2-associated breast cancer share homologous recombination deficiency, but also have independent and potentially actionable roles. Novel drugs with innovative mechanism of action, lacking cross-resistance with other used agents are needed for BRCA 1/2 MBC. Trabectedin (TR) and its analog, lurbinectedin (L), have shown to be active in BRCA 1/2 MBC. This study was sought to determine if there was a difference in activity of these agents between BRCA1 and 2 carriers. Methods: Safety and efficacy in MBC BRCA 1/2 were analyzed in 2 separate phase II trials of single agent TR and L. Results: 88 patients were evaluated: 34 with TR, 54 with L. Median age: 46 and 43, respectively. Median (range) prior chemotherapy lines: TR, 4 (1-10); L, 2 (0-5). Clinical responses were seen in the 2 trials (see table) and were higher in BRCA2 than in BRCA1 (33% vs 9% with TR and 61% vs 26% with L). Main adverse event was myelosuppression (grade 3-4 neutropenia / thrombocytopenia / febrile neutropenia: TR, 62.1%/24.3%/10.8% L, 66.7%/20.4%/20.4%). Non-hematological toxicity was mostly grade 1-2: fatigue, nausea/vomiting and high transaminases (grade 3/4 TR, 40.5%, L 18.5%). Conclusions: Remarkable activity of trabectedin and lurbinectedin as single agents was observed in BRCA 2 associated MBC. This finding warrants further investigation. One potential mechanistic rationale is the role of both lurbinectedin and BRCA 2 in transcription. Safety was acceptable and manageable in both studies. Clinical trial information: NCT01525589. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document