PubMed · 3882598
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
J Phillip, S Dralle. 1985. [Preparation for colonoscopy--which methods are suitable?].. https://pubmed.ncbi.nlm.nih.gov/3882598/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
Cancer is a disease characterized by genomic instability and aberrant DNA repair. Poly (ADP-ribose) polymerase-1 (PARP-1) represents a well-established therapeutic target, particularly in ovarian and prostate cancer. However, the currently approved PARP inhibitors face challenges such as resistance, toxicity, and reduced efficacy. The search for alternative scaffolds has therefore become increasingly urgent. In this study, we used an integrated approach combining computer-aided methods to search for potential lead compounds among emodin-based anthraquinone derivatives as PARP-1 inhibitors. Using a PASS-based QSAR approach, drug-likeness prediction, and in silico ADMET assessment, we pre-screened a large set of anthraquinones and identified several potential hits for interaction with PARP-1. These hits were studied using molecular docking with the PARP-1 catalytic domain (PDB ID: 7KK4). The most stable and compact complexes were further explored by 500 ns molecular dynamics (MD) simulations and various dynamic properties (RMSD, RMSF, Rg, SASA, MolSA, hydrogen bonds, PCA, DCCM). The key finding of this study is that several emodin-derived anthraquinones exhibited binding behavior and ADMET profiles comparable to, or better than, the reference PARP-1 inhibitor. Among them, CID-10425624 emerged as the most promising candidate, exhibiting stable binding, reduced conformational fluctuation, compact complex formation, persistent hydrogen-bond interactions, and enhanced dynamic residue correlations within the PARP-1 catalytic domain. These findings suggest that the anthraquinone scaffold can provide a valuable starting point for developing structurally distinct PARP-1 inhibitors. In summary, this study identified several emodin-derived anthraquinones, particularly CID-10425624, as computationally prioritized lead candidates for PARP-1 inhibition, providing a novel anthraquinone-based scaffold for further experimental validation and optimization.
Quinones with one, two and three aromatic rings are a new class of micromolar non-peptidic inhibitors of HIV-1 proteinase, an enzyme essential for replication of Human Immunodeficiency Virus and an important drug target for AIDS. Substituted anthraquinones bearing hydroxyl substituents on one of their three rings were the most potent of these inhibitors. Comparisons with other small non-peptidic inhibitors that are now emerging, together with enzyme kinetic data indicating that alizarin is a competitive inhibitor, suggest that anthraquinones bind in the active-site groove of HIV-1 proteinase.
The mode of interaction of the ketocarboxyl-group-recognizing enzyme oxaloacetate decarboxylase (OXAD) from Pseudonomas sp., with purpose-designed (keto)-carboxyl-terminal biomimetic monochlorotriazinyl-dyes (BM) and parent dichlorotriazinyl-dye Vilmafix blue A-R (VBAR) was investigated. Kinetic inhibition studies and determinations of KD values of the respective dye-enzyme complex from both difference spectra and enzyme inactivation studies were employed. Substratemimetic (biomimetic) dye-ligands bear a terminal (keto)carboxyl-moiety linked to the reactive chlorotriazine ring, thus mimicking the organic acid substrate of OXAD. Dichlorotriazine-dye VBAR bound specifically and irreversibly to OXAD (k3 0.22 min-1). The inactivation of OXAD by VBAR was enhanced in the presence of 1 mM Mn+2 (KD 67.2 microM) but in the absence of metal cation was decreased (KD 117 microM). The metal cation behaves as a partial competitive activator. Either of binary complexes dye.OXAD and OXAD.Mn+2 could be formed first, prior to addition of the third constituent to form the ternary complex, although the former route may be favored. The pKa of the catalytically important nucleophile, involved in the specific modification of OXAD, was calculated to 7.4. Biomimetic monochlorotriazine dyes have failed to inactivate OXAD but inhibited competitively the inactivation by VBAR. When compared to commercial VBAR and Cibacron blue 3GA (CB3GA), all BM ligands show lower KD values, therefore, higher affinity for the enzyme. OXAD preferred binding to BM dyes which exhibited a large aliphatic ketocarboxyl-terminal biomimetic moiety. Dye binding to OXAD was accompanied by a characteristic spectral change in the range 550-800 nm. Electrostatic interactions appeared to play a dominant role in the dye.OXAD complex. The BM ligand bearing an aminoethyloxamate as its terminal biomimetic moiety (BM7) displayed the highest affinity (KD 0.5 or 7.0 microM; approx 10-fold decrease over CB3GA). The BM7 ligand behaved as competitive inhibitor (Ki 98 microM) of oxaloacetate decarboxylase against oxaloacetate as variable substrate.