1,721,023 research outputs found
An Outline on Environmentally Degradable Polymeric Materials and Plastics. State of the Art on Future Perspectives
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Molecular dynamics study on the conformation stability of laminaran oligomers in various solvents
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DESIGN OF PEPTIDOMIMETIC INHIBITORS OF ASPARTIC PROTEASE OF HIV-1 CONTAINING -PHEpsiPRO- CORE AND DISPLAYING FAVOURABLE ADME-RELATED PROPERTIES
No full textAspartic protease (PR) of HIV-1 virus represents a valid therapeutic target for the design of antiviral
agents suitable for treatment of AIDS.We have designed peptidomimetic PR inhibitors containing a novel
dihydroxyethylenediamine –Phe-C[CHOH–CHOH]-Pro– core using molecular modelling approach that
predicts the inhibitory potencies (ICpre
50 ) in terms of computed relative enzyme–inhibitor complexation
Gibbs free energies (DDGcomp). The modelling approach considers not only the enzyme–inhibitor
interactions, but includes also the solvent and entropic effects affecting the enzyme inhibition. The
objectives of this study were to optimize the number and type of flanking residues that occupy the S3, S2
and S20, S30 positions in the PR binding pocket and to select potent lead candidates, which display also
favourable ADME-related properties. The structure-based designwas combined with a synthetic strategy
used to prepare a training set of 10 analogues sharing the –PheCPro– core. This strategy couples
stereochemical control with full flexibility in the choice of the flanking residues and in vitro activity
assays. A QSAR model correlating calculated DDGcomp with the measured ICexp
50 values for the training set
was prepared and confirmed that our computational approach can serve for reliable prediction of PR
inhibitory potencies of peptidomimetics. The appropriate choice of the flanking residues allowed us to
design virtual lead compounds, such as FP14, FP23 and FP76, with reduced molecular weight, predicted
inhibitory potencies in the picomolar range, promising ADME profiles and a potential to escape drug
resistance due to favourable interactions with the PR backbone
Efficient inhibition of HIV-1 aspartic protease by synthetic, computer designed peptide mimetics
No full textInhibitors of HIV-1 aspartic protease, an enzyme which is essential for viral processing and maturation, represent an important new type of anti-AIDS drug. To be effective, these must be potent and selec tive, must present a suitable pharmacological profile with respect to drug uptake and clearance, and should also be synthesizeable in good yields. We have developed a design method based on computer aided modification of a reference compound for which the crystal structure of the complex with the enzyme is known. After relaxation of the new structures to an optimized geometry, the complexation energy is calculated, relative to that of the reference inhibitor, taking into account all aspects of the interaction, including solvation. This affords a numerical prediction of the putative effectiveness of the new structure as an inhibitor, relative to that of the reference structure, and thus allows us to rapidly evaluate modifications that could result in increased potency and reduce the number of compounds that it is actually necessary to synthesize so as to obtain useful lead compounds for drug development. In an initial study, we have determined the role of flanking residues in modulating inhibition, for hexapeptide mimetics with a central, reduced amide non-cleavable bond. The structure was based on that of the reference inhibitor MVT-101. We have found that by tuning the residues flanking the central bond, the complexation energy could be markedly improved, and have determined that the putatively optimal structure should contain an aromatic residue (Phe or Tyr) at positions p1 and p1', immediately flanking the central bond, a hydrophobic residue at P2, a glutamic acid residue at P2', and an aromatic residue (Phe, Tyr or Trp) at positions P3 and P3', most distant from the central bond. Synthesis of a series of inhibitors containing these modifications was carried out entirely in the solid phase, using Fmoc type chemistry, on a polyethylene glycol/polystyrene resin, and in vitro enzyme inhibition assays have confirmed the computer-based predictions. In particular, it was possible to obtain several inhibitors with potency in the low nanomolar range, an improvement of several orders of magnitude with respect to the parent compound
Computational Design of New Cyclic Urea Inhibitors for Improved Binding of HIV-1 Aspartic Protease.
No full textA computational study of the resistance of HIV- aspartic protease to the inhibitors ABT-538 and VX-478 and design of new analogues
No full textBIOCHEM. BIOPHYS. RES. COMMUN
The disordered conformation of κ -carrageenan in solution as depicted by NMR experiments and molecular mechanics.
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