82 research outputs found
Targeting the Major Groove of the Palindromic d(GGCGCC)2 Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators
GC-rich sequences are recurring motifs in oncogenes and retroviruses, and
could be targeted by non-covalent major-groove therapeutic ligands. We
considered the palindromic sequence d(G1G2C3G4C5C6)2, and designed several
oligopeptide derivatives of the anti-cancer intercalator mitoxantrone. The
stability of their complexes with a 18-mer oligonucleotide encompassing this
sequence in its center was validated using polarizable molecular dynamics. We
report the most salient structural features of two novel compounds, having a
dialkylammonium group as a side-chain on both arms. The anthraquinone ring is
intercalated in the central d(CpG)2 sequence with its long axis perpendicular
to that of the two base-pairs. On each strand, this enables each ammonium group
to bind in-register to O6/N7 of the two facing G bases upstream. We
subsequently designed tris-intercalating derivatives, each dialkylammonium
substituted with a connector to an N9-aminoacridine intercalator extending our
target range from six- to a ten-base pair palindromic sequence,
d(C1G2G3G4C5G6C7C8C9G10)2. The structural features of the complex of the most
promising derivative are reported. The present design strategy paves the way
for designing intercalator-oligopeptide derivatives with an even higher
selectivity, targeting an increased number of DNA bases, going beyond ten
Design of Group IIA Secreted/Synovial Phospholipase A2 Inhibitors: An Oxadiazolone Derivative Suppresses Chondrocyte Prostaglandin E2 Secretion
Group IIA secreted/synovial phospholipase A2 (GIIAPLA2) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E2 (PGE2), the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-yl)pentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA2, along with their chemical synthesis and results from PLA2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA2 affinities than did C1, and such predictions were confirmed by in vitro PLA2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1β-stimulated PGE2 secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints
Toward a Separate Reproduction of the Contributions to the Hartree−Fock and DFT Intermolecular Interaction Energies by Polarizable Molecular Mechanics with the SIBFA Potential
International audienc
Complexes of thiomandelate and captopril mercaptocarboxylate inhibitors to metallo-β-lactamase by polarizable molecular mechanics. Validation on model binding sites by quantum chemistry
International audienc
- …