title: Exploring the Binding Affinity of Novel Syringic Acid Analogues and Critical Determinants of Selectivity as Potent Proteasome Inhibitors.
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.
authors.forename: Srinivasulu
authors.initials: S
authors.lastname: Cheemanapalli
authors.forename: C M
authors.initials: CM
authors.lastname: Anuradha
authors.forename: P
authors.initials: P
authors.lastname: Madhusudhana
authors.forename: M
authors.initials: M
authors.lastname: Mahesh
authors.affiliation: School of Biotechnology, School of Chemical and Biological Sciences, REVA University, Bangalore 560064, K.A., India.
authors.forename: Pongali B
authors.initials: PB
authors.lastname: Raghavendra
authors.affiliation: Department of Biochemistry/ DBT-Bioinformatics Infrastructure Facility, Sri Krishnadevaraya University, Anantapuramu 515003, A.P., India.
authors.forename: Chitta S
authors.initials: CS
authors.lastname: Kumar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019611:Archaeoglobus fulgidus / Q000201:enzymology; D001665:Binding Sites / Q000187:drug effects; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology; D012485:Salmonella typhi / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D061988:Proteasome Inhibitors; D005707:Gallic Acid; C001945:syringic acid; D046988:Proteasome Endopeptidase Complex