3 research outputs found
Thermodynamic Characterization of Hydration Sites from Integral Equation-Derived Free Energy Densities: Application to Protein Binding Sites and Ligand Series
Water
molecules play an essential role for mediating interactions
between ligands and protein binding sites. Displacement of specific
water molecules can favorably modulate the free energy of binding
of proteināligand complexes. Here, the nature of water interactions
in protein binding sites is investigated by 3D RISM (three-dimensional
reference interaction site model) integral equation theory to understand
and exploit local thermodynamic features of water molecules by ranking
their possible displacement in structure-based design. Unlike molecular
dynamics-based approaches, 3D RISM theory allows for fast and noise-free
calculations using the same detailed level of soluteāsolvent
interaction description. Here we correlate molecular water entities
instead of mere site density maxima with local contributions to the
solvation free energy using novel algorithms. Distinct water molecules
and hydration sites are investigated in multiple proteināligand
X-ray structures, namely streptavidin, factor Xa, and factor VIIa,
based on 3D RISM-derived free energy density fields. Our approach
allows the semiquantitative assessment of whether a given structural
water molecule can potentially be targeted for replacement in structure-based
design. Finally, PLS-based regression models from free energy density
fields used within a 3D-QSAR approach (CARMa - comparative analysis
of 3D RISM Maps) are shown to be able to extract relevant information
for the interpretation of structureāactivity relationship (SAR)
trends, as demonstrated for a series of serine protease inhibitors
Targeting Dynamic Pockets of HIVā1 Protease by Structure-Based Computational Screening for Allosteric Inhibitors
We
present the discovery of low molecular weight inhibitors of
human immunodeficiency virus 1 (HIV-1) protease subtype B that were
identified by structure-based virtual screening as ligands of an allosteric
surface cavity. For pocket identification and prioritization, we performed
a molecular dynamics simulation and observed several flexible, partially
transient surface cavities. For one of these presumable ligand-binding
pockets that are located in the so-called āhinge regionā
of the identical protease chains, we computed a receptor-derived pharmacophore
model, with which we retrieved fragment-like inhibitors from a screening
compound pool. The most potent hit inhibited protease activity in
vitro in a noncompetitive mode of action. Although attempts failed
to crystallize this ligand bound to the enzyme, the study provides
proof-of-concept for identifying innovative tool compounds for chemical
biology by addressing flexible protein models with receptor pocket-derived
pharmacophore screening
Identification of High-Affinity P2Y<sub>12</sub> Antagonists Based on a Phenylpyrazole Glutamic Acid Piperazine Backbone
A series of novel, highly potent P2Y<sub>12</sub> antagonists
as
inhibitors of platelet aggregation based on a phenylpyrazole glutamic
acid piperazine backbone is described. Exploration of the structural
requirements of the substituents by probing the structureāactivity
relationship along this backbone led to the discovery of the <i>N</i>-acetyl-(<i>S</i>)-proline cyclobutyl amide moiety
as a highly privileged motif. Combining the most favorable substituents
led to remarkably potent P2Y<sub>12</sub> antagonists displaying not
only low nanomolar binding affinity to the P2Y<sub>12</sub> receptor
but also a low nanomolar inhibition of platelet aggregation in the
human platelet rich plasma assay with IC<sub>50</sub> values below
50 nM. Using a homology and a three-dimensional quantitative structureāactivity
relationship model, a binding hypothesis elucidating the impact of
several structural features was developed