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

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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Empagliflozin and Doxorubicin Synergistically Inhibit the Survival of Triple-Negative Breast Cancer Cells via Interfering with the mTOR Pathway and Inhibition of Calmodulin: In Vitro and Molecular Docking Studies

ACS Pharmacology & Translational Science ◽

10.1021/acsptsci.0c00144 ◽

2020 ◽

Vol 3 (6) ◽

pp. 1330-1338 ◽

Cited By ~ 1

Author(s):

Shenouda G. Eliaa ◽

Ahmed A. Al-Karmalawy ◽

Rasha M. Saleh ◽

Mohamed F. Elshal

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Docking Studies ◽

Mtor Pathway ◽

Molecular Docking Studies

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Design, Synthesis, Antiproliferative Evaluation, and Molecular Docking Studies of N-(3-Hydroxyindole)-Appended β-Carbolines/Tetrahydro-β-Carbolines Targeting Triple-Negative and Non-Triple-Negative Breast Cancer

ACS Omega ◽

10.1021/acsomega.0c01226 ◽

2020 ◽

Vol 5 (45) ◽

pp. 28907-28917

Author(s):

Bharvi Sharma ◽

Sourav Taru Saha ◽

Shanen Perumal ◽

Liang Gu ◽

Oluwakemi Ebenezer ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Docking Studies ◽

Design Synthesis ◽

Molecular Docking Studies

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Chemo-informatics activity prediction, ligand based drug design, Molecular docking and pharmacokinetics studies of some series of 4, 6-diaryl-2-pyrimidinamine derivatives as anti-cancer agents

Bulletin of the National Research Centre ◽

10.1186/s42269-021-00631-w ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

Sagiru Hamza Abdullahi ◽

Adamu Uzairu ◽

Muhammad Tukur Ibrahim ◽

Abdullahi Bello Umar

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Qsar Model ◽

Docking Studies ◽

Standard Drug ◽

Reference Drug ◽

Molecular Docking Studies ◽

Lipinski’S Rule ◽

Adverse Health Effects ◽

Orally Bioavailable

Abstract Background The most well-known cause of cancer deaths identified in female is breast cancer. Several drugs approved by the food and drug administration (FDA) for the treatment of breast cancer may have adverse health effects. This research is aimed at developing a QSAR model and utilize it to predict the inhibitive activities of newly designed novel compounds, examine their ADMET and drug-likeness properties and carry out molecular docking studies between the designed compounds and the VEGFR-2 receptors in order to identify the essential amino acid residues involved in protein–ligand interactions and possible mechanism of action of the designed compounds. Results The first model was selected as the best because of its fitness statistically with the following assessment parameters: R2train = 0.832, R2adj = 0.79, R2ext = 0.62, Q2 = 0.68, and LOF = 0.14509. Compound 11 was selected as a template to design new powerful compounds based on its low residual and high pIC50 values. Majority of the designed compounds has predicted pIC50 greater than that of the lead compound and the standard drug (Sunitinib) used as reference. Molecular docking studies results of the designed compounds revealed that they have higher docking scores than the template and the reference drug (Sunitinib) and are found to bind to the VEGFR-2 receptor in a similar manner to the reference drug. Pharmacokinetics and ADMET properties revealed that the designed compounds passed drug-likeness criteria because they did not violate more than 1 Lipinski’s rule of Five, They are uniformly distributed to the brain and are assumed to penetrate the central nervous system and finally they are all found to non-toxic and orally bioavailable. Conclusion The developed model was therefore found to be efficient in predicting the pIC50 of Anti breast cancer compounds that are yet to be synthesized and it also help in reducing the cost and synthetic duration the compounds. The result of this research confirmed that the designed compounds may be developed as novel VEGFR-2 inhibitors.

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Design, Synthesis and Molecular Docking Studies of 4-{3-[2-(2-Morpholin-4-yl-ethoxy)phenyl]-5-phenyl-pyrazol-1-yl}-benzenesulfonamide as Anti-Breast Cancer Agent

Asian Journal of Organic & Medicinal Chemistry ◽

10.14233/ajomc.2020.ajomc-p271 ◽

2020 ◽

Vol 5 (4) ◽

pp. 301-306

Author(s):

Praveen Kumar ◽

Jai Prakash Kumar ◽

Juhi Barnwal ◽

Ritu Singh

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Anticancer Activity ◽

Mtt Assay ◽

Cancer Cell Line ◽

Docking Studies ◽

Mcf7 Cells ◽

Standard Drug ◽

Molecular Docking Studies ◽

Cancer Agent

Novel 4-{3-[2-(2-morpholin-4-yl-ethoxy)phenyl]-5-phenyl-pyrazol- 1-yl}benzenesulfonamide (7) was synthesized and evaluated for its anti-breast cancer activity. It was prepared by cyclocondensation reaction of morpholine-substituted β-diketone, 1-[2-(2-morpholin-4-yl-ethoxy)- phenyl]-3-phenyl-propane-1,3-dione (3) with 4-hydrazinobenzenesulfonamide hydrochloride (6). Chemical structure of titled compound (7) was confirmed by FTIR, 1H & 13C NMR and HRMS spectroscoic analyses. The anticancer activity of titled compound 7 was evaluated against MCF-7 breast cancer cell line by MTT assay. Molecular docking was performed to predict its plausible binding with the estrogen receptor α(ERα) using Molecular Operating Environment 2019.0101 software. The MTT assay results showed that titled compound 7 exhibited better anticancer activity against MCF7 cells (IC50: 4.25 μM) than standard drug, 4-hydroxytamoxifen (IC50: 8.22 μM). Results of molecular docking studies were found in good agreement with the results of anticancer evaluation, as the binding score of titled compound 7 (-16.9872 kcal/mol) was lower as compared to 4-hydroxytamoxifen (-15.1112 kcal/mol). The new cationic interaction of titled compound 7 with Trp383 and hydrogen bonding interaction with Phe404 in active site of ERα made its anticancer activity better than 4-hydroxytamoxifen. Thus, 4-{3-[2-(2-morpholin-4-yl-ethoxy)phenyl]-5-phenyl-pyrazol- 1-yl}benzenesulfonamide (7) was emerged as a potent anti-breast cancer agent.

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Design, synthesis and molecular docking studies of thymol based 1,2,3-triazole hybrids as thymidylate synthase inhibitors and apoptosis inducers against breast cancer cells

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2021.116136 ◽

2021 ◽

pp. 116136

Author(s):

Mohammad Mahboob Alam ◽

Azizah M. Malebari ◽

Syed Nazreen ◽

Thikryat Neamatallah ◽

Abdulraheem SA Almalki ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Cancer Cells ◽

Thymidylate Synthase ◽

Breast Cancer Cells ◽

Docking Studies ◽

Design Synthesis ◽

Molecular Docking Studies ◽

Thymidylate Synthase Inhibitors

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QSAR, molecular docking, design, and pharmacokinetic analysis of 2-(4-fluorophenyl) imidazol-5-ones as anti-breast cancer drug compounds against MCF-7 cell line

Journal of Bioenergetics and Biomembranes ◽

10.1007/s10863-020-09858-0 ◽

2020 ◽

Vol 52 (6) ◽

pp. 475-494

Author(s):

Hadiza Abdulrahman Lawal ◽

Adamu Uzairu ◽

Sani Uba

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Cell Line ◽

Docking Studies ◽

Cancer Drug ◽

Pharmacokinetic Analysis ◽

Analysis Model ◽

Molecular Docking Studies ◽

Derivatives Of ◽

Mcf 7

AbstractThe anti-proliferative activities of Novel series of 2-(4-fluorophenyl) imidazol-5-ones against MCF-7 breast cancer cell line were explored via in-slico studies which includes Quantitative structure–activity relationship QSAR, molecular docking studies, designing new compounds, and analyzing the pharmacokinetics properties of the designed compounds. From the QSAR analysis, model number one emerged the best as seen from the arithmetic assessments of (R2) = 0.6981, (R2adj) = 0.6433, (Q2) = 0.5460 and (R2pred) of 0.5357. Model number one was used in designing new derivative compounds, with higher effectiveness against estrogen positive breast cancer (MCF-7 cell line). The Molecular docking studies between the derivatives and Polo-like kinases (Plk1) receptor proved that the derivatives of 2-(4-fluorophenyl) imidazol-5-ones bind tightly to the receptor, thou ligand 24 and 27 had the highest binding affinities of −8.8 and − 9.1 kcal/mol, which was found to be higher than Doxorubicin with a docking score of −8.0 kcal/mol. These new derivatives of 2-(4-fluorophenyl) imidazol-5-ones shall be excellent inhibitors against (plk1). The pharmacokinetics analysis performed on the new structures revealed that all the structures passed the test and also the Lipinski rule of five, and they could further proceed to pre-clinical tests. They both revealed a revolution in medicine for developing novel anti-breast cancer drugs against MCF-7 cell line.

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Mibefradil inhibits the proliferation of triple-negative breast cancer by targeting AURKA to regulate apoptosis signal pathway

10.21203/rs.3.rs-210031/v1 ◽

2021 ◽

Author(s):

Xu Han ◽

Xiujuan Qu ◽

Beixing Liu ◽

Yizhe Wang ◽

Yang Cheng ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Molecular Docking ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Therapeutic Drug ◽

Specific Gene ◽

In Vivo Models

Abstract Background: Triple negative breast cancer (TNBC) is a tumor characterized by high recurrence and mortality, but without effective targeted therapy. It is urgent to explore new treatment strategy to improve the efficacy of TNBC therapy. Methods: Transcriptomic profiling datasets of TNBC were used for screening TNBC specific gene sets. Drug prediction was performed in Connectivity map (CMap) database. Molecular docking method was used for analyzing drug targets. In vitro and in vivo models of TNBC were constructed to examine the drug efficacy. Results: We screened out Mibefradil, a T-type Ca2+ channel blocker, might be a potential therapeutic drug for TNBC by transcriptomics and bioinformatics analysis, and verified that Mibefradil could inhibit the proliferation of TNBC cells by inducing apoptosis and cell cycle arrest. Furthermore, by network pharmacology and molecular docking analysis, AURKA was predicted as the most possible drug target of Mibefradil. Finally, it was proved that Mibefradil treatment could induce apoptosis by decreasing protein expression and phosphorylation level of AURKA in vitro and in vivo. Conclusions: Mibefradil played anti-cancer role in TNBC cells by targeting to AURKA to induce cell cycle and apoptosis. Our results repurposed Mibefradil as a potential targeted drug of TNBC and provided a fundamental research for a novel strategy TNBC treatment.

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BACH2 expression associates with survival in triple negative breast cancer.

10.31219/osf.io/7e52n ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Microarray Data ◽

Leucine Zipper ◽

Triple Negative ◽

Breast Cancer Patients ◽

Basic Leucine Zipper ◽

Primary Tumors ◽

Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of BTB and CNC homology 1, basic leucine zipper transcription factor 2, encoded by BACH2 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, BACH2 expression was correlated with overall survival in patients with breast cancer. BACH2 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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Microwave-Assisted Synthesis, Molecular Docking Studies and Biological Evaluation of Benzothiazole Containing Novel Indole Derivatives

Asian Journal of Chemistry ◽

10.14233/ajchem.2021.23404 ◽

2021 ◽

Vol 33 (11) ◽

pp. 2755-2761

Author(s):

Shaheen Sultana ◽

P. Pandian ◽

B. Rajkamal

Keyword(s):

Molecular Docking ◽

Reaction Mechanism ◽

Anticancer Activity ◽

Mannich Base ◽

Docking Studies ◽

Biological Evaluation ◽

Indole Derivatives ◽

Standard Drug ◽

Molecular Docking Studies ◽

Microwave Assisted

The synthesis of novel indole derivatives 4a-o using a microwave assisted method via Schiff’s base and Mannich base reaction mechanism was described. Compounds 3a-c were synthesized via reaction of 2-amino benzothiazole with substituted isatin by Schiff base reaction mechanism. Also, indole derivatives 4a-o were synthesized via reaction of compounds 3a-c with substituted benzaldehydes by Mannich base reaction. The biological potentials of the newly synthesized indole derivatives were evaluated for their anthelmintic activity and in vitro anticancer activity by MTT assay. The anticancer activity results suggested that indole derivatives 4c-o have activity against MCF-7 and SKOV3 cells in comparison with doxorubicin as standard drug. Furthermore, the molecular docking studies of these novel derivatives of indole showed good agreement with the biological results when their binding pattern and affinity towards the active site of EGFR was also investigated.

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