TY - JOUR
T1 - An Integrative Informatics Approach to Explain the Mechanism of Action of N1-(Anthraquinon-2-yl) Amidrazones as BCR/ABL Inhibitors
AU - Sabbah, Dima A.
AU - Hajjo, Rima
AU - Sweidan, Kamal
AU - Zhong, Haizhen A.
N1 - Funding Information:
The authors gratefully acknowledge the financial support from the study was financially supported by Al-Zaytoonah University of Jordan Deanship of Scientific Research and Graduate Studies (Grant number: 3/6/2014).
Publisher Copyright:
© 2021 Bentham Science Publishers.
PY - 2021/10
Y1 - 2021/10
N2 - Background: Drugs incorporating heterocyclic chemical skeletons possess a plethora of therapeutic activities such as anticancer, antimicrobial, antihypertensive, and antipsychiatric effects. It is becoming routine, nowadays, to use cheminformatics and bioinformatics methods to elucidate the mechanism(s) of action of such drugs. Objective: This study aimed to probe the activity of a recently published series of N1-(anthraquinon-2-yl) amidrazone piperazine derivatives employing computational strategies[1], identify their structural basis of binding to BCR/ABL kinase domain, and explain their anticancer activities in human breast adenocarcinoma (MCF-7) and chronic myelogenous leukemia (K562) cell lines. Methods: We applied an in silico integrative informatics approach integrating molecular descriptors, docking studies, cheminformatics, and network analysis. Results: Our results highlighted the possible involvement of the BCR/ABL and DRD2 pathways in the anticancer activity of the studied compounds, and induced fit docking (IFD) indicated that the BCR/ABL kinase domain is a putative drug target. Additionally, high-scoring docking poses identified a unique network of hydrogen bonding with amino acids Y253, K271, E286, V299, L301, T315, M318, I360, R362, V379, and D3810. Conclusion: Using an integrative informatics approach to characterize our anticancer compounds, we were able to explain the biological differences between synthesized and biologically validated amidrazone piperazine anticancer agents. We were also able to postulate a mechanism of action of this novel group of anticancer agents.
AB - Background: Drugs incorporating heterocyclic chemical skeletons possess a plethora of therapeutic activities such as anticancer, antimicrobial, antihypertensive, and antipsychiatric effects. It is becoming routine, nowadays, to use cheminformatics and bioinformatics methods to elucidate the mechanism(s) of action of such drugs. Objective: This study aimed to probe the activity of a recently published series of N1-(anthraquinon-2-yl) amidrazone piperazine derivatives employing computational strategies[1], identify their structural basis of binding to BCR/ABL kinase domain, and explain their anticancer activities in human breast adenocarcinoma (MCF-7) and chronic myelogenous leukemia (K562) cell lines. Methods: We applied an in silico integrative informatics approach integrating molecular descriptors, docking studies, cheminformatics, and network analysis. Results: Our results highlighted the possible involvement of the BCR/ABL and DRD2 pathways in the anticancer activity of the studied compounds, and induced fit docking (IFD) indicated that the BCR/ABL kinase domain is a putative drug target. Additionally, high-scoring docking poses identified a unique network of hydrogen bonding with amino acids Y253, K271, E286, V299, L301, T315, M318, I360, R362, V379, and D3810. Conclusion: Using an integrative informatics approach to characterize our anticancer compounds, we were able to explain the biological differences between synthesized and biologically validated amidrazone piperazine anticancer agents. We were also able to postulate a mechanism of action of this novel group of anticancer agents.
KW - BCR/ABL
KW - Chemical-protein interactions
KW - Cheminformatics
KW - DRD2
KW - IFD
KW - K562
KW - MCF-7
KW - Molecular descriptors
KW - N1-(Anthraquinon-2-yl) Amidrazones
KW - Network analysis
KW - Similarity searching
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U2 - 10.2174/1573409916666200819113444
DO - 10.2174/1573409916666200819113444
M3 - Article
C2 - 32814537
AN - SCOPUS:85123324279
VL - 17
SP - 817
EP - 830
JO - Current Computer-Aided Drug Design
JF - Current Computer-Aided Drug Design
SN - 1573-4099
IS - 6
ER -