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.
Anti-Cancer Agents in Medicinal Chemistry
Title:Exploring the Binding Affinity of Novel Syringic Acid Analogues and Critical Determinants of Selectivity as Potent Proteasome Inhibitors
Volume: 16 Issue: 11
Author(s): Srinivasulu Cheemanapalli, C. M. Anuradha, P. Madhusudhana, M. Mahesh, Pongali B. Raghavendra and Chitta S. Kumar
Affiliation:
Keywords: β5 proteasome, DFT-density functional theory, multiple myeloma, tetramethylsilane, ubiquitin-proteasome pathway.
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.
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Cheemanapalli Srinivasulu, Anuradha M. C., Madhusudhana P., Mahesh M., Raghavendra B. Pongali and Kumar S. Chitta, Exploring the Binding Affinity of Novel Syringic Acid Analogues and Critical Determinants of Selectivity as Potent Proteasome Inhibitors, Anti-Cancer Agents in Medicinal Chemistry 2016; 16 (11) . https://dx.doi.org/10.2174/1871520616666160513131928
DOI https://dx.doi.org/10.2174/1871520616666160513131928 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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