Exploring Citrus sinensis Phytochemicals as Potential Inhibitors for Breast Cancer Genes BRCA1 and BRCA2 Using Pharmacophore Modeling, Molecular Docking, MD Simulations, and DFT Analysis

Article

作者: Brogi, Simone ; Zia, Mehreen ; Rashid, Maryam ; Shahab, Muhammad ; Dauelbait, Musaab ; Salamatullah, Ahmad Mohammad ; Shafiq, Nusrat ; Parveen, Shagufta ; Bourhia, Mohammed ; Farooq, Ariba

BACKGROUNDStructure-activity relationship (SAR) is considered to be an effective in silico approach when discovering potential antagonists for breast cancer due to gene mutation. Major challenges are faced by conventional SAR in predicting novel antagonists due to the discovery of diverse antagonistic compounds. Methodologyand Results: In predicting breast cancer antagonists, a multistep screening of phytochemicals isolated from the seeds of the Citrus sinensis plant was applied using feasible complementary methodologies. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed through the Flare project, in which conformational analysis, pharmacophore generation, and compound alignment were done. Ten hit compounds were obtained through the development of the 3D-QSAR model. For exploring the mechanism of action of active compounds against cocrystal inhibitors, molecular docking analysis was done through Molegro software (MVD) to identify lead compounds. Three new proteins, namely, 1T15, 3EU7, and 1T29, displayed the best Moldock scores. The quality of the docking study was assessed by a molecular dynamics simulation. Based on binding affinities to the receptor in the docking studies, three lead compounds (stigmasterol P8, epoxybergamottin P28, and nobiletin P29) were obtained, and they passed through absorption, distribution, metabolism, and excretion (ADME) studies via the SwissADME online service, which proved that P28 and P29 were the most active allosteric inhibitors with the lowest toxicity level against breast cancer. Then, density functional theory (DFT) studies were performed to measure the active compound's reactivity, hardness, and softness with the help of Gaussian 09 software.CONCLUSIONSThis multistep screening of phytochemicals revealed high-reliability antagonists of breast cancer by 3D-QSAR using flare, docking analysis, and DFT studies. The present study helps in providing a proper guideline for the development of novel inhibitors of BRCA1 and BRCA2.

2024-01-01·Breast Cancer Research and Treatment

Analysing potent biomarkers along phytochemicals for breast cancer therapy: an in silico approach

Article

作者: Kaur, Parwinder ; Shekar, Nivruthi ; Vuong, Paton

AbstractPurposeThis research focused on the identification of herbal compounds as potential anti-cancer drugs, especially for breast cancer, that involved the recognition of Notch downstream targets NOTCH proteins (1–4) specifically expressed in breast tumours as biomarkers for prognosis, along with P53 tumour antigens, that were used as comparisons to check the sensitivity of the herbal bio-compounds.MethodsAfter investigating phytochemical candidates, we employed an approach for computer-aided drug design and analysis to find strong breast cancer inhibitors. The present study utilized in silico analyses and protein docking techniques to characterize and rank selected bio-compounds for their efficiency in oncogenic inhibition for use in precise carcinomic cell growth control.ResultsSeveral of the identified phytocompounds found in herbs followed Lipinski’s Rule of Five and could be further investigated as potential medicinal molecules. Based on the Vina score obtained after the docking process, the active compound Epigallocatechin gallate in green tea with NOTCH (1–4) and P53 proteins showed promising results for future drug repurposing. The stiffness and binding stability of green tea pharmacological complexes were further elucidated by the molecular dynamic simulations carried out for the highest scoring phytochemical ligand complex.ConclusionThe target-ligand complex of green tea active compound Epigallocatechin gallate with NOTCH (1–4) had the potential to become potent anti-breast cancer therapeutic candidates following further research involving wet-lab experiments.

2023-08-07·Journal of the Egyptian National Cancer Institute

Ligand-based drug design of quinazolin-4(3H)-ones as breast cancer inhibitors using QSAR modeling, molecular docking, and pharmacological profiling.

Article

作者: Uzairu, Adamu ; Umar, Abdullahi Bello ; Uba, Sani ; Shallangwa, Gideon Adamu ; Abdullahi, Sagiru Hamza

BACKGROUNDBreast cancer is the most common tumor among females globally. Its prevalence is growing around the world, and it is alleged to be the leading cause of cancer death. Approved anti-breast cancer drugs display several side effects and resistance during the early treatment stage. Hence, there is a need for the development of more effective and safer drugs. This research was aimed at designing more potent quinazolin-4(3H)-one molecules as breast cancer inhibitors using a ligand-based design approach, studying their modes of interaction with the target enzyme using molecular docking simulation, and predicting their pharmacological properties.METHODSThe QSAR model was developed using a series of quinazoline-4(3H)-one derivatives by utilizing Material Studio v8.0 software and validated both internally and externally. Applicability domain virtual screening was utilized in selecting the template molecule, which was structurally modified to design more potent molecules. The inhibitive capacities of the design molecules were predicted using the developed model. Furthermore, molecular docking was performed with the EGFR target active site residues, which were obtained from the protein data bank online server (PDB ID: 2ITO) using Molegro Virtual Docker (MVD) software. SwissADME and pkCSM online sites were utilized in predicting the pharmacological properties of the designed molecules.RESULTSFour QSAR models were generated, and the first model was selected due to its excellent internal and external statistical parameters as follows: R² = 0.919, R²_adj = 0.898, Q²_cv = 0.819, and R²_pred = 0.7907. The robustness of the model was also confirmed by the result of the Y-scrambling test performed with cR²p = 0.7049. The selected model was employed to design seven molecules, with compound 4 (pIC₅₀ = 5.18) adopted as the template. All the designed compounds exhibit better activities ranging from pIC₅₀ = 5.43 to 5.91 compared to the template and Doruxybucin (pIC₅₀ = 5.35). The results of molecular docking revealed better binding with the EGFR target compared with the template and Doruxybucin. The designed compounds exhibit encouraging therapeutic applicability, as evidenced by the findings of pharmacological property prediction.CONCLUSIONSThe designed derivatives could be utilized as novel anti-breast cancer agents.

项与 Breast cancer therapeutics(Theraclone Sciences) 相关的新闻（医药）

2023-02-16

·BioSpace

Adaptimmune Announces Changes to Board of Directors

Philadelphia, Pennsylvania and Oxford, United Kingdom--(News - February 16, 2023) - Adaptimmune Therapeutics plc (NASDAQ: ADAP), a leader in T-cell therapy to treat cancer, today announced that Kristen M. Hege, M.D. will join its board of directors. In addition, Dr. Tal Zaks, who has served as a Non-Executive Director since 2016, will be stepping down from the board of directors. "On behalf of the Board and management, I want to welcome Kristen and also thank Tal for his support and contributions over the past six years as he has helped guide Adaptimmune from an early-stage company to one on the verge of commercializing its first product," said Adrian Rawcliffe, Adaptimmune's Chief Executive Officer. "Kristen is a fantastic addition to our Board as we seek to develop a full pipeline of products for multiple solid tumor indications. Not only does Kristen have a deep knowledge of immuno-oncology and cell therapy specifically, she also knows how to develop these products with a keen knowledge of the business landscape." "I am delighted to welcome Kristen to the Board," commented David Mott, Adaptimmune's Chairman. "Her substantial immuno-oncology experience will be particularly valuable as the Company progresses toward marketed products. I also want to thank Tal for his hard work and dedication and wish him all the best." Dr. Hege brings more than two decades of oncology clinical leadership experience to Adaptimmune's board. Currently, she is Senior Vice President, Early Clinical Development, Hematology/Oncology & Cell Therapy at Bristol Myers Squibb (BMS). Dr. Hege joined BMS following acquisition of Celgene in November 2019. She is responsible for global early clinical development and oversight of BMS's pipeline and partnered assets, including cell therapies, in all hematologic and solid tumor indications from first-in-human studies through human proof-of-concept. Dr. Hege will be retiring from BMS in March. She is also a professor of Hematology/Oncology and an attending physician at the University of California, San Francisco (UCSF). Prior to Celgene, Dr. Hege was a senior medical advisor to development-stage biotech companies including Aragon and Theraclone. A pioneer in immuno-oncology, she began her career at Cell Genesys Inc. where she spent 14 years in various roles of increasing responsibility. Dr. Hege holds a M.D. from the UCSF School of Medicine and a B.A. in biochemistry from Dartmouth College. She completed her residency in Internal Medicine at Brigham and Women's Hospital and completed a subspecialty fellowship in Hematology and Oncology at UCSF. She was also a visiting bone marrow transplant fellow at the Fred Hutchinson Cancer Research Center. Dr. Hege also serves as a board member of Mersana Therapeutics, Inc and Graphite Bio Inc. About Adaptimmune Adaptimmune is a clinical-stage biopharmaceutical company focused on the development of novel cancer immunotherapy products for people with cancer. The Company's unique SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell platform enables the engineering of T-cells to target and destroy cancer across multiple solid tumors. Forward-Looking Statements This release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 (PSLRA). These forward-looking statements involve certain risks and uncertainties. Such risks and uncertainties could cause our actual results to differ materially from those indicated by such forward-looking statements, and include, without limitation: the success, cost and timing of our product development activities and clinical trials and our ability to successfully advance our TCR therapeutic candidates through the regulatory and commercialization processes. For a further description of the risks and uncertainties that could cause our actual results to differ materially from those expressed in these forward-looking statements, as well as risks relating to our business in general, we refer you to our Annual Report on Form 10-K filed with the Securities and Exchange Commission for the year ended December 31, 2021, our Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and other filings with the Securities and Exchange Commission. The forward-looking statements contained in this press release speak only as of the date the statements were made and we do not undertake any obligation to update such forward-looking statements to reflect subsequent events or circumstances. Adaptimmune Contact Investor Relations Juli P. Miller, Ph.D. - VP, Corporate Affairs and Investor Relations T: +1 215 825 9310 M: +1 215 460 8920 Juli.Miller@adaptimmune.com Media Relations Dana Lynch, Senior Director of Corporate Communications M: +1 267 990 1217 Dana.Lynch@adaptimmune.com To view the source version of this press release, please visit

高管变更免疫疗法并购细胞疗法

100 项与 Breast cancer therapeutics(Theraclone Sciences) 相关的药物交易

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