TY - JOUR
T1 - Computational and Biophysical Characterization of Heterocyclic Derivatives of Anthraquinone against Human Aurora Kinase A
AU - Singh, Mandeep
AU - Haque, Md Anzarul
AU - Tikhomirov, Alexander S.
AU - Shchekotikhin, Andrey E.
AU - Das, Uddipan
AU - Kaur, Punit
N1 - Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/11/8
Y1 - 2022/11/8
N2 - Human Aurora kinase A (AurA) has recently garnered the attention of researchers worldwide as a promising effective mitotic drug target for its involvement in cancer and related inflammatory anomalies. This study has explored the binding affinity of newly identified heteroarene-fused anthraquinone derivatives against AurA. Molecular docking analyses showed that all the heteroanthraquinone compounds bind to AurA with different affinities. Molecular dynamics simulation studies revealed that the compounds maintained relatively stable binding modes in the active site pocket while inducing minimal conformational changes in the AurA structure, interacting with key residues through several noncovalent interactions, including hydrogen bonds. Fluorescence spectroscopy and biolayer interferometry binding assays with synthesized compounds against recombinantly expressed AurA further verified their binding efficacy. Naphthoisatine 3 proved to be the best binder, with compounds anthraimidazole 5 and anthrathiophene 2 showing comparable results. Overall, this study indicates decent binding of heterocyclic derivatives of anthraquinone with the target AurA, which can further be assessed by performing enzymatic assays and cellular studies. The studies also highlight the applicability of the heteroarene-fused anthraquinone scaffold to construct selective and potent inhibitors of Aurora kinases after necessary structural modifications for the development of new anticancer drugs.
AB - Human Aurora kinase A (AurA) has recently garnered the attention of researchers worldwide as a promising effective mitotic drug target for its involvement in cancer and related inflammatory anomalies. This study has explored the binding affinity of newly identified heteroarene-fused anthraquinone derivatives against AurA. Molecular docking analyses showed that all the heteroanthraquinone compounds bind to AurA with different affinities. Molecular dynamics simulation studies revealed that the compounds maintained relatively stable binding modes in the active site pocket while inducing minimal conformational changes in the AurA structure, interacting with key residues through several noncovalent interactions, including hydrogen bonds. Fluorescence spectroscopy and biolayer interferometry binding assays with synthesized compounds against recombinantly expressed AurA further verified their binding efficacy. Naphthoisatine 3 proved to be the best binder, with compounds anthraimidazole 5 and anthrathiophene 2 showing comparable results. Overall, this study indicates decent binding of heterocyclic derivatives of anthraquinone with the target AurA, which can further be assessed by performing enzymatic assays and cellular studies. The studies also highlight the applicability of the heteroarene-fused anthraquinone scaffold to construct selective and potent inhibitors of Aurora kinases after necessary structural modifications for the development of new anticancer drugs.
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U2 - 10.1021/acsomega.2c00740
DO - 10.1021/acsomega.2c00740
M3 - Article
C2 - 36385832
AN - SCOPUS:85141446559
SN - 2470-1343
VL - 7
SP - 39603
EP - 39618
JO - ACS Omega
JF - ACS Omega
IS - 44
ER -