Integrated molecular modeling and dynamics approaches revealed potential natural inhibitors of NF-κB transcription factor as breast cancer therapeutics

被引:1
作者
Zubair, Muhammad [1 ]
Khalil, Sidra [1 ]
Rasul, Ijaz [1 ]
Nadeem, Habibullah [1 ]
Noor, Fatima [1 ]
Ahmad, Sajjad [2 ]
Alrumaihi, Faris [3 ]
Allemailem, Khaled S. [3 ]
Almatroudi, Ahmad [3 ]
Alshehri, Faez Falah [4 ]
Alshehri, Zafer Saad [4 ]
机构
[1] Govt Coll Univ, Dept Bioinformat & Biotechnol, Faisalabad, Pakistan
[2] Abasyn Univ, Dept Hlth & Biol Sci, Peshawar, Pakistan
[3] Qassim Univ, Coll Appl Med Sci, Dept Med Labs, Buraydah, Saudi Arabia
[4] Shaqra Univ, Coll Appl Med Sci, Aldawadmi, Saudi Arabia
关键词
Breast cancer; NF-kappa B; structure-based 3D pharmacophore model; virtual screening; molecular docking; molecular dynamic simulation; FREE-ENERGY CALCULATIONS; DOCKING; TARGET; PROGRESSION; MODULATION; MECHANICS; DISCOVERY; INSIGHTS; CELLS; QSAR;
D O I
10.1080/07391102.2023.2214209
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Breast cancer is a silent killer malady among women and a serious economic burden in health care management. A case of breast cancer is diagnosed among women every 19 s, and every 74 s, a woman dies of breast cancer somewhere in the world. Despite the pop-up of progressive research, advanced treatment approaches, and preventive measures, breast cancer remains amplifying ailment. The nuclear factor kappa B (NF-?B) is a key transcription factor that links inflammation with cancer and is demonstrated as being involved in the tumorigenesis of breast cancer. The NF-?B transcription factor family in mammals consists of five proteins; c-Rel, RelA(p65), RelB, NF-?B1(p50), and NF-?B2(p52). The antitumor effect of NF-?B has also been explored in breast cancer, however, the actual treatment for breast cancer is yet to be discovered. This study is attributed to the identification of novel drug targets against breast cancer by targeting c-Rel, RelA(p65), RelB, NF-?B1(p50), and NF-?B2(p52) proteins. To identify the putative active compounds, a structure-based 3D pharmacophore model to the protein active site cavity was generated followed by virtual screening, molecular docking, and molecular dynamics (MD) simulation. Initially, a library of 45000 compounds were docked against the target protein and five compounds namely Z56811101, Z653426226, Z1097341967, Z92743432, and Z464101066 were selected for further analysis. The relative binding affinity of Z56811101, Z653426226, Z1097341967, Z92743432, and Z464101066 with NF-?B1 (p50), NF-?B2 (p52), RelA (p65), RelB, and c-Rel proteins were -6.8, -8, -7.0, -6.9, and -7.2 kcal/mol, respectively which remained stable throughout the simulations of 200 ns. Furthermore, all of these compounds depict maximum drug-like properties. Therefore, the proposed compounds can be a potential candidate for patients with breast cancer, but, experimental validation is needed to ensure their safety.
引用
收藏
页码:14715 / 14729
页数:15
相关论文
共 75 条
[1]   Anticancer potential of phytochemicals against breast cancer: Molecular docking and simulation approach [J].
Ahmed, Bilal ;
Ashfaq, Usman Ali ;
ul Qamar, Muhammad Tahir ;
Ahmad, Matloob .
BANGLADESH JOURNAL OF PHARMACOLOGY, 2014, 9 (04) :545-550
[2]   Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CLpro [J].
Alamri, Mubarak A. ;
ul Qamar, Muhammad Tahir ;
Mirza, Muhammad Usman ;
Bhadane, Rajendra ;
Alqahtani, Safar M. ;
Muneer, Iqra ;
Froeyen, Matheus ;
Salo-Ahen, Outi M. H. .
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2021, 39 (13) :4936-4948
[3]   Discovery of anti-MERS-CoV small covalent inhibitors through pharmacophore modeling, covalent docking and molecular dynamics simulation [J].
Alamri, Mubarak A. ;
ul Qamar, Muhammad Tahir ;
Afzal, Obaid ;
Alabbas, Alhumaidi B. ;
Riadi, Yassine ;
Alqahtani, Safar M. .
JOURNAL OF MOLECULAR LIQUIDS, 2021, 330
[4]   Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches [J].
Alamri, Mubarak A. ;
ul Qamar, Muhammad Tahir ;
Mirza, Muhammad Usman ;
Alqahtani, Safar M. ;
Froeyen, Matheus ;
Chen, Ling-Ling .
JOURNAL OF PHARMACEUTICAL ANALYSIS, 2020, 10 (06) :546-559
[5]   Chemical-informatics approach to COVID-19 drug discovery: Monte Carlo based QSAR, virtual screening and molecular docking study of somein-housemolecules as papain-like protease (PLpro) inhibitors [J].
Amin, Sk. Abdul ;
Ghosh, Kalyan ;
Gayen, Shovanlal ;
Jha, Tarun .
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2021, 39 (13) :4764-4773
[6]   Molecular Docking and Simulation Studies of Antidiabetic Agents Devised from Hypoglycemic Polypeptide-P of Momordica charantia [J].
Arif, Rawaba ;
Ahmad, Sajjad ;
Mustafa, Ghulam ;
Mahrosh, Hafiza Salaha ;
Ali, Muhammad ;
ul Qamar, Muhammad Tahir ;
Dar, Hafiza Rabia .
BIOMED RESEARCH INTERNATIONAL, 2021, 2021
[7]   ProTox-II: a webserver for the prediction of toxicity of chemicals [J].
Banerjee, Priyanka ;
Eckert, Andreas O. ;
Schrey, Anna K. ;
Preissner, Robert .
NUCLEIC ACIDS RESEARCH, 2018, 46 (W1) :W257-W263
[8]   Inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions [J].
Ben-Baruch, A .
BREAST CANCER RESEARCH, 2003, 5 (01) :31-36
[9]   Tumor-associated stromal cells as key contributors to the tumor microenvironment [J].
Bussard, Karen M. ;
Mutkus, Lysette ;
Stumpf, Kristina ;
Gomez-Manzano, Candelaria ;
Marini, Frank C. .
BREAST CANCER RESEARCH, 2016, 18
[10]   Discovery of a New Mcl-1 Protein Inhibitor through the QSAR Approach and Molecular Docking Study [J].
Byadi, Said ;
Sadik, Karima ;
Hachim, Mouhi Eddine ;
Daoudi, Mohamed ;
Podlipnik, Crtomir ;
Aboulmouhajir, Aziz .
ADVANCED THEORY AND SIMULATIONS, 2022, 5 (08)