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

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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Molecular docking and 3D-QSAR-based virtual screening of flavonoids as potential aromatase inhibitors against estrogen-dependent breast cancer

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2014.912152 ◽

2014 ◽

Vol 33 (4) ◽

pp. 804-819 ◽

Cited By ~ 20

Author(s):

Manika Awasthi ◽

Swati Singh ◽

Veda P. Pandey ◽

Upendra N. Dwivedi

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Virtual Screening ◽

Aromatase Inhibitors ◽

3D Qsar

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Reverse Screening Bioinformatics Approach to Identify Potential Anti Breast Cancer Targets Using Thymoquinone from Neutraceuticals Black Cumin Oil

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190124155359 ◽

2019 ◽

Vol 19 (5) ◽

pp. 599-609 ◽

Cited By ~ 1

Author(s):

Sumathi Sundaravadivelu ◽

Sonia K. Raj ◽

Banupriya S. Kumar ◽

Poornima Arumugamand ◽

Padma P. Ragunathan

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Cycle ◽

Cell Death ◽

In Silico ◽

Chemotherapeutic Agents ◽

Normal Cells ◽

Black Cumin ◽

In Silico Docking ◽

Wide Range

Background: Functional foods, neutraceuticals and natural antioxidants have established their potential roles in the protection of human health and diseases. Thymoquinone (TQ), the main bioactive component of Nigella sativa seeds (black cumin seeds), a plant derived neutraceutical was used by ancient Egyptians because of their ability to cure a variety of health conditions and used as a dietary food supplement. Owing to its multi targeting nature, TQ interferes with a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Additionally, TQ can specifically sensitize tumor cells towards conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy) and simultaneously minimize therapy-associated toxic effects in normal cells besides being cost effective and safe. TQ was found to play a protective role when given along with chemotherapeutic agents to normal cells. Methods: In the present study, reverse in silico docking approach was used to search for potential molecular targets for cancer therapy. Various metastatic and apoptotic targets were docked with the target ligand. TQ was also tested for its anticancer activities for its ability to cause cell death, arrest cell cycle and ability to inhibit PARP gene expression. Results: In silico docking studies showed that TQ effectively docked metastatic targets MMPs and other apoptotic and cell proliferation targets EGFR. They were able to bring about cell death mediated by apoptosis, cell cycle arrest in the late apoptotic stage and induce DNA damage too. TQ effectively down regulated PARP gene expression which can lead to enhanced cancer cell death. Conclusion: Thymoquinone a neutraceutical can be employed as a new therapeutic agent to target triple negative breast cancer which is otherwise difficult to treat as there are no receptors on them. Can be employed along with standard chemotherapeutic drugs to treat breast cancer as a combinatorial therapy.

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Steroidal aromatase inhibitors inhibit growth of hormone-dependent breast cancer cells by inducing cell cycle arrest and apoptosis

APOPTOSIS ◽

10.1007/s10495-013-0879-6 ◽

2013 ◽

Vol 18 (11) ◽

pp. 1426-1436 ◽

Cited By ~ 12

Author(s):

Cristina Amaral ◽

Carla Varela ◽

Margarida Borges ◽

Elisiário Tavares da Silva ◽

Fernanda M. F. Roleira ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Aromatase Inhibitors ◽

Breast Cancer Cells ◽

Cycle Arrest ◽

Steroidal Aromatase Inhibitors

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Pharmacophore modeling, virtual screening, and 3D-QSAR studies on a series of non-steroidal aromatase inhibitors

Medicinal Chemistry Research ◽

10.1007/s00044-014-1257-9 ◽

2014 ◽

Vol 24 (5) ◽

pp. 1901-1915 ◽

Cited By ~ 5

Author(s):

Huiding Xie ◽

Kaixiong Qiu ◽

Xiaoguang Xie

Keyword(s):

Virtual Screening ◽

Aromatase Inhibitors ◽

3D Qsar ◽

Pharmacophore Modeling ◽

Qsar Studies ◽

Steroidal Aromatase Inhibitors

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Relevance of Aromatase Inhibitors in Breast Cancer Treatment

Current Topics in Medicinal Chemistry ◽

10.2174/1568026621666210701143445 ◽

2021 ◽

Vol 21 ◽

Author(s):

Ankita Sood ◽

Damanpreet Kaur Lang ◽

Rajwinder Kaur ◽

Balraj Saini ◽

Sandeep Arora

Keyword(s):

Breast Cancer ◽

Aromatase Inhibitors ◽

Breast Tissue ◽

Positive Impact ◽

Treatment Options ◽

Living Standards ◽

Efficacious Treatment ◽

Clinical Resistance ◽

Steroidal Aromatase Inhibitors ◽

Near Future

: Efficacious treatment for breast cancer is still a challenge despite the presence of various treatment options. Aromatase enzyme present in the breast tissue is responsible for estrogen formation from androgens. Aromatase inhibitors manifest remarkably ameliorated therapeutic efficacy as compared to the current therapeutic options available and exhibit a better safety profile as compared to the other drugs. Clinical resistance to aromatase inhibitors is perceived as a lack of growth inhibition by aromatase inhibitors treatment and cancer therapy becomes ineffective in causing a decrease in the size of the tumor. Naturally extracted aromatase inhibitors have a huge positive impact on vitality and living standards. This review article highlights the particulars about the currently approved steroidal and non-steroidal aromatase inhibitors for clinical use, adverse effects associated with their use and approach to tackling the problem, various strategies to overcome aromatase inhibitors resistance, information on the synthesis of various peculiar aromatase inhibitors which can prove as highly efficient and potent drugs in the near future and the drugs of natural and semi-synthetic origin which can demonstrate to be more efficient, potent and less-toxic than conventional therapy.

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