Exploring the Binding Affinity of Novel Syringic Acid Analogues and Critical Determinants of Selectivity as Potent Proteasome Inhibitors

Author(s): Srinivasulu Cheemanapalli, C. M. Anuradha, P. Madhusudhana, M. Mahesh, Pongali B. Raghavendra, Chitta S. Kumar

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 16 , Issue 11 , 2016

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Graphical Abstract:


Syringic acid, a known plant phenolic compound and its analogues are known to possess high proteasome inhibitory activity. In the current work, we describe synthesis, characterization, DFT, docking of syringic acid (SA) and analogues (SAA1 and SAA2) and biological effects were studied. Syringic acid and its analogues were docked for the first time with the crystal structures of β5 proteasome of diverse eukaryotic organisms. Among all proteasomes, the humanoid proteasome showed the highest degree of docking conformation and low inhibition constant (Ki). SAA2 specifically displayed binding to the N-terminal Thr1 residue in the S1 pocket of Mus musculus β5 proteasome along with threonine, lysine and arginine; conventionally involved major amino acid residues in ligand binding. The geometrical properties (B3LYP/6- 31g (d, p)) and electrostatic potentials of molecules were computed using DFT calculations. A detailed molecular picture of the compounds and its interactions was obtained from NBO analysis. SA-analogues elucidated potent antioxidant activities and good antibacterial activity. In-vitro DNA binding studies revealed that all molecules had strong binding at the major groove of dsDNA. In the view of medical applicability, proteasome inhibition is an important therapeutic strategy for various types of cancers. Therefore, current discoveries may encourage the rational design and development of new chemical entities of syringic acid based chemotherapeutics.

Keywords: β5 proteasome, DFT-density functional theory, multiple myeloma, tetramethylsilane, ubiquitin-proteasome pathway.

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Article Details

Year: 2016
Page: [1496 - 1510]
Pages: 15
DOI: 10.2174/1871520616666160513131928
Price: $65

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