Phage-derived peptides as new epitopes of breast cancer

Epidemiological data on death rates and incidence of Breast Cancer (BC) are still alarming, highlighting the need for new strategies of diagnosis and therapy. Our group has previously described a new antibody in Fab format, FabC4, for diagnostics, staging, and prognosis of BC. Objectives: To map the FabC4 epitopes and evaluate those for their diagnostic potential. Methods: A Phage Display-based assay against FabC4 was performed to identify and characterize peptides as new epitopes of BC. The selected peptides were also evaluated for their reactivity to patient sera through ELISA assay. We finally conducted molecular docking to assess the best conformation of FabC4-epitopes. Results: Four peptides-displaying phages differentiated sera samples from 50 patients with BC, benign disease, and from healthy women. The corresponding peptides were chemically synthesized (pA5, pA7, pC4 and pD6) and bound to FabC4. The peptide pD6 differentiated the neoplastic samples from benign and healthy sera. Molecular docking analyzes confirmed the interaction between FabC4 and the selected peptides. Conclusion: We have successfully mapped the FabC4 epitopes with diagnostic potential, opening new avenues for the understanding and treatment of BC.

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Structure Guided Molecular Docking Assisted Alignment Dependent 3DQSAR Study on Steroidal Aromatase Inhibitors (SAIs) as Anti-breast Cancer Agents

Letters in Drug Design & Discovery ◽

10.2174/1570180815666181010101024 ◽

2019 ◽

Vol 16 (7) ◽

pp. 808-817 ◽

Cited By ~ 3

Author(s):

Laxmi Banjare ◽

Sant Kumar Verma ◽

Akhlesh Kumar Jain ◽

Suresh Thareja

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Aromatase Inhibitors ◽

Direct Synthesis ◽

3D Qsar ◽

Chemotherapeutic Agents ◽

Modeling Tools ◽

Data Set ◽

Wide Range ◽

Steroidal Aromatase Inhibitors

Background: In spite of the availability of various treatment approaches including surgery, radiotherapy, and hormonal therapy, the steroidal aromatase inhibitors (SAIs) play a significant role as chemotherapeutic agents for the treatment of estrogen-dependent breast cancer with the benefit of reduced risk of recurrence. However, due to greater toxicity and side effects associated with currently available anti-breast cancer agents, there is emergent requirement to develop target-specific AIs with safer anti-breast cancer profile. Methods: It is challenging task to design target-specific and less toxic SAIs, though the molecular modeling tools viz. molecular docking simulations and QSAR have been continuing for more than two decades for the fast and efficient designing of novel, selective, potent and safe molecules against various biological targets to fight the number of dreaded diseases/disorders. In order to design novel and selective SAIs, structure guided molecular docking assisted alignment dependent 3D-QSAR studies was performed on a data set comprises of 22 molecules bearing steroidal scaffold with wide range of aromatase inhibitory activity. Results: 3D-QSAR model developed using molecular weighted (MW) extent alignment approach showed good statistical quality and predictive ability when compared to model developed using moments of inertia (MI) alignment approach. Conclusion: The explored binding interactions and generated pharmacophoric features (steric and electrostatic) of steroidal molecules could be exploited for further design, direct synthesis and development of new potential safer SAIs, that can be effective to reduce the mortality and morbidity associated with breast cancer.

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Synthesis, In-vitro and Docking Analysis of C-3 substituted Coumarin Analogues as Anticancer Agents C-3 Substituted Coumarins as Anticancer Agents

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200120114641 ◽

2020 ◽

Vol 16 ◽

Author(s):

Anuradha Thakur ◽

Kamalpreet Kaur ◽

Praveen Sharma ◽

Ramit Singla ◽

Sandeep Singh ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Anticancer Agents ◽

Proliferative Activity ◽

Binding Interaction ◽

Diverse Range ◽

Mcf 7 ◽

Substituted Coumarins

Background: Breast cancer (BC) is a leading cause of cancer-related deaths in women next to skin cancer. Estrogen receptors (ERs) play an important role in the progression of BC. Current anticancer agents have several drawbacks such as serious side effects and the emergence of resistance to chemotherapeutic drugs. As coumarins possess minimum side effect along with multi-drug reversal activity, it has a tremendous ability to regulate a diverse range of cellular pathways that can be explored for selective anticancer activity. Objectives: Synthesis and evaluation of new coumarin analogues for anti-proliferative activity on human breast cancer cell line MCF-7 along with exploration of binding interaction of the compounds for ER-α target protein by molecular docking. Method: In this study, the anti-proliferative activity of C-3 substituted coumarins analogues (1-17) has been evaluated against estrogen receptor-positive MCF-7 breast cancer cell lines. Molecular interactions and ADME study of the compounds were analyzed by using Schrodinger software. Results: Among the synthesized analogues 12 and 13 show good antiproliferative activity with IC50 values 1and 1.3 µM respectively. Molecular docking suggests a remarkable binding pose of all the seventeen compounds. Compounds 12 and 13 were found to exhibit dock score of -4.10 kcal/mol and -4.38 kcal/mol respectively. Conclusion: Compounds 12 and 13 showed the highest activity followed by 1 and 5. ADME properties of all compounds were in the acceptable range. The active compounds can be taken for lead optimization and mechanistic interventions for their in vivo study in the future.

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Design, Synthesis, In Vitro Anti-cancer Activity, ADMET Profile and Molecular Docking of Novel Triazolo[3,4-a]phthalazine Derivatives Targeting VEGFR-2 Enzyme

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180412123833 ◽

2018 ◽

Vol 18 (8) ◽

pp. 1184-1196 ◽

Cited By ~ 13

Author(s):

Abdel-Ghany A. El-Helby ◽

Helmy Sakr ◽

Rezk R.A. Ayyad ◽

Khaled El-Adl ◽

Mamdouh M. Ali ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Cell Lines ◽

Colon Adenocarcinoma ◽

Human Colon ◽

Kinase Assay ◽

Anticancer Activities ◽

In Silico Admet ◽

Human Colon Adenocarcinoma ◽

Mcf 7

Background: Extensive studies were reported in the synthesis of several phthalazine derivatives as promising anticancer agents as potent VEGFR-2 inhibitors. Vatalanib (PTK787) was the first anilinophthalazine published derivative as a potent inhibitor of VEGFR. The discovery of vatalanib as a clinical candidate led to the design and synthesis of different anilinophthalazine derivatives as potent inhibitors for VEGFR-2. The objective of present research work is the synthesis of new agents with the same essential pharmacophoric features of the reported and clinically used VEGFR-2 inhibitors (e.g vatalanib and sorafenib). The main core of our molecular design rationale comprised bioisosteric modification strategies of VEGFR-2 inhibitors at four different positions. </P><P> Material and Methods: A correlation between structure and biological activity of our designed phthalazines was established using molecular docking and VEGFR-2 kinase assay. Results and Discussion: In view of their expected anticancer activity, novel triazolo[3,4-a]phthalazine derivatives 5-6a-o and 3-substituted-bis([1,2,4]triazolo)[3,4-a:4',3'-c]phthalazines 9a-b were designed, synthesized and evaluated for their anti-proliferative activity against two human tumor cell lines HCT-116 human colon adenocarcinoma and MCF-7 breast cancer. It was found that, compound 6o the most potent derivative against both HCT116 and MCF-7 cancer cell lines. Compounds 6o, 6m, 6d and 9b showed the highest anticancer activities against HCT116 human colon adenocarcinoma with IC50 of 7±0.06, 13±0.11, 15±0.14 and 23±0.22 µM respectively while compounds 6o, 6d, 6a and 6n showed the highest anticancer activities against MCF-7 breast cancer with IC50 of 16.98±0.15, 18.2±0.17, 57.54±0.53 and 66.45±0.67 µM respectively. Sorafenib as a highly potent VEGFR-2 inhibitor was used as a reference drug with IC50 of 5.47±0.3 and 7.26±0.3 µM respectively. Nine compounds were further evaluated for their VEGFR-2 inhibitory activity. Compounds 6o, 6m, 6d and 9b emerged as the most active counterparts against VEGFR-2 with IC50 values of 0.1±0.01, 0.15±0.02, 0.28±0.03 and 0.38±0.04 µM, respectively comparable to that of sorafenib (IC50 = 0.1±0.02) µM. Furthermore, molecular docking studies were carried out for all synthesized compounds to investigate their binding pattern and predict their binding affinities towards VEGFR-2 active site. In silico ADMET studies were calculated for the tested compounds. Most of our designed compounds exhibited good ADMET profile. Conclusion: The obtained results showed that, the most active compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective VEGFR-2 inhibitors with higher anticancer analogs.

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QSAR, molecular docking studies, ligand-based design and pharmacokinetic analysis on Maternal Embryonic Leucine Zipper Kinase (MELK) inhibitors as potential anti-triple-negative breast cancer (MDA-MB-231 cell line) drug compounds

Bulletin of the National Research Centre ◽

10.1186/s42269-021-00541-x ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

Hadiza Abdulrahman Lawal ◽

Adamu Uzairu ◽

Sani Uba

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Triple Negative Breast Cancer ◽

Leucine Zipper ◽

Triple Negative ◽

Qsar Model ◽

Docking Studies ◽

Model Parameters ◽

Standard Drug ◽

Molecular Docking Studies

Abstract Background Cancer of the breast is known to be among the top spreading diseases on the globe. Triple-negative breast cancer is painstaking the most destructive type of mammary tumor because it spreads faster to other parts of the body, with high chances of early relapse and mortality. This research would aim at utilizing computational methods like quantitative structure–activity relationship (QSAR), performing molecular docking studies and again to further design new effective molecules using the QSAR model parameters and to analyze the pharmacokinetics “drug-likeliness” properties of the new compounds before they could proceed to pre-clinical trials. Results The QSAR model of the derivatives was highly robust as it also conforms to the least minimum requirement for QSAR model from the statistical assessments of (R2) = 0.6715, (R2adj) = 0.61920, (Q2) = 0.5460 and (R2pred) of 0.5304, and the model parameters (AATS6i and VR1_Dze) were used in designing new derivative compounds with higher potency. The molecular docking studies between the derivative compounds and Maternal Embryonic Leucine Zipper Kinase (MELK) protein target revealed that ligand 2, 9 and 17 had the highest binding affinities of − 9.3, − 9.3 and − 8.9 kcal/mol which was found to be higher than the standard drug adriamycin with − 7.8 kcal/mol. The pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test and also the Lipinski rule of five. Conclusions The results obtained from the QSAR mathematical model of parthenolide derivatives were used in designing new derivatives compounds that were more effective and potent. The molecular docking result of parthenolide derivatives showed that compounds 2, 9 and 17 had higher docking scores than the standard drug adriamycin. The compounds would serve as the most promising inhibitors (MELK). Furthermore, the pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test (ADME and other physicochemical properties) and they also adhered to the Lipinski rule of five. This gives a great breakthrough in medicine in finding the cure to triple-negative breast cancer (MBA-MD-231 cell line).

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Targeting the Roots of Recurrence: New Strategies for Eliminating Therapy-Resistant Breast Cancer Stem Cells

Cancers ◽

10.3390/cancers13010054 ◽

2020 ◽

Vol 13 (1) ◽

pp. 54

Author(s):

Margaret L. Dahn ◽

Paola Marcato

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Breast Cancer Stem Cells ◽

Self Renewal ◽

New Strategies

Cancer stem cells (CSCs) are functionally defined in our laboratories by their impressive tumor-generating and self-renewal capacity; clinically, CSCs are of interest because of their enhanced capacity to evade conventional therapies [...]

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Diagnostic potential of hypoxia-induced genes in liquid biopsies of breast cancer patients

Scientific Reports ◽

10.1038/s41598-021-87897-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Carlos Henrique F. Peiró ◽

Matheus M. Perez ◽

Glauco S. A. de Aquino ◽

Jéssica F. A. Encinas ◽

Luiz Vinícius de A. Sousa ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Glucose Transporter ◽

Carbonic Anhydrases ◽

Breast Cancer Patients ◽

Gene Expressions ◽

Liquid Biopsies ◽

Healthy Women ◽

Diagnostic Potential ◽

Laboratory Tool

AbstractIn tumor cells, higher expression of glucose transporter proteins (GLUT) and carbonic anhydrases (CAIX) genes is influenced by hypoxia-induced factors (HIF).Thus, we aimed to study the expression profile of these markers in sequential peripheral blood collections performed in breast cancer patients in order to verify their predictive potential in liquid biopsies. Gene expressions were analyzed by qPCR in tumor and blood samples from 125 patients and 25 healthy women. Differential expression was determined by the 2(−ΔCq) method. Expression of HIF-1α and GLUT1 in the blood of breast cancer patients is significantly higher (90–91 and 160–161 fold increased expression, respectively; p < 0.0001) than that found in healthy women. Their diagnostic power was confirmed by ROC curve. CAIX is also more expressed in breast cancer women blood, but its expression was detected only in a few samples. But none of these genes could be considered predictive markers. Therefore, evaluation of the expression of HIF-1α and GLUT1 in blood may be a useful laboratory tool to complement the diagnosis of breast cancer, in addition to being useful for follow-up of patients and of women with a family history of breast cancer.

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Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance

Cancers ◽

10.3390/cancers13112634 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2634

Author(s):

Beatriz Soldevilla ◽

Angeles López-López ◽

Alberto Lens-Pardo ◽

Carlos Carretero-Puche ◽

Angeles Lopez-Gonzalvez ◽

...

Keyword(s):

Metabolic Pathways ◽

Metabolic Networks ◽

Tca Cycle ◽

Metabolomic Profile ◽

Diagnostic Potential ◽

The Tca Cycle ◽

Novel Biomarkers ◽

Potential Methods ◽

Clinical Potential ◽

First Time

Purpose: High-throughput “-omic” technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research.

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Synthesis, DFT Calculations, Antiproliferative, Bactericidal Activity and Molecular Docking of Novel Mixed-Ligand Salen/8-Hydroxyquinoline Metal Complexes

Molecules ◽

10.3390/molecules26164725 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4725

Author(s):

Badriah Saad Al-Farhan ◽

Maram T. Basha ◽

Laila H. Abdel Rahman ◽

Ahmed M. M. El-Saghier ◽

Doaa Abou El-Ezz ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Metal Complexes ◽

Wide Spectrum ◽

Mixed Ligand ◽

Molecular Formula ◽

Hep G2 ◽

Anticancer Activities ◽

Azomethine Group ◽

Ic50 Values

Despite the common use of salens and hydroxyquinolines as therapeutic and bioactive agents, their metal complexes are still under development. Here, we report the synthesis of novel mixed-ligand metal complexes (MSQ) comprising salen (S), derived from (2,2′-{1,2-ethanediylbis[nitrilo(E) methylylidene]}diphenol, and 8-hydroxyquinoline (Q) with Co(II), Ni(II), Cd(II), Al(III), and La(III). The structures and properties of these MSQ metal complexes were investigated using molar conductivity, melting point, FTIR, 1H NMR, 13C NMR, UV–VIS, mass spectra, and thermal analysis. Quantum calculation, analytical, and experimental measurements seem to suggest the proposed structure of the compounds and its uncommon monobasic tridentate binding mode of salen via phenolic oxygen, azomethine group, and the NH group. The general molecular formula of MSQ metal complexes is [M(S)(Q)(H2O)] for M (II) = Co, Ni, and Cd or [M(S)(Q)(Cl)] and [M(S)(Q)(H2O)]Cl for M(III) = La and Al, respectively. Importantly, all prepared metal complexes were evaluated for their antimicrobial and anticancer activities. The metal complexes exhibited high cytotoxic potency against human breast cancer (MDA-MB231) and liver cancer (Hep-G2) cell lines. Among all MSQ metal complexes, CoSQ and LaSQ produced IC50 values (1.49 and 1.95 µM, respectively) that were comparable to that of cisplatin (1.55 µM) against Hep-G2 cells, whereas CdSQ and LaSQ had best potency against MDA-MB231 with IC50 values of 1.95 and 1.43 µM, respectively. Furthermore, the metal complexes exhibited significant antimicrobial activities against a wide spectrum of both Gram-positive and -negative bacterial and fungal strains. The antibacterial and antifungal efficacies for the MSQ metal complexes, the free S and Q ligands, and the standard drugs gentamycin and ketoconazole decreased in the order AlSQ > LaSQ > CdSQ > gentamycin > NiSQ > CoSQ > Q > S for antibacterial activity, and for antifungal activity followed the trend of LaSQ > AlSQ > CdSQ > ketoconazole > NiSQ > CoSQ > Q > S. Molecular docking studies were performed to investigate the binding of the synthesized compounds with breast cancer oxidoreductase (PDB ID: 3HB5). According to the data obtained, the most probable coordination geometry is octahedral for all the metal complexes. The molecular and electronic structures of the metal complexes were optimized theoretically, and their quantum chemical parameters were calculated. PXRD results for the Cd(II) and La(III) metal complexes indicated that they were crystalline in nature.

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