6 research outputs found
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
Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach
A structure-guided hybridization
approach using two privileged
substructures gave instant access to a new series of tankyrase inhibitors.
The identified inhibitor <b>16</b> displays high target affinity
on tankyrase 1 and 2 with biochemical and cellular IC<sub>50</sub> values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity
toward other poly (ADP-ribose) polymerase enzymes. The identified
inhibitor shows a favorable in vitro ADME profile as well as good
oral bioavailability in mice, rats, and dogs. Critical for the approach
was the utilization of an appropriate linker between 1,2,4-triazole
and benzimidazolone moieties, whereby a cyclobutyl linker displayed
superior affinity compared to a cyclohexane and phenyl linker
Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach
A structure-guided hybridization
approach using two privileged
substructures gave instant access to a new series of tankyrase inhibitors.
The identified inhibitor <b>16</b> displays high target affinity
on tankyrase 1 and 2 with biochemical and cellular IC<sub>50</sub> values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity
toward other poly (ADP-ribose) polymerase enzymes. The identified
inhibitor shows a favorable in vitro ADME profile as well as good
oral bioavailability in mice, rats, and dogs. Critical for the approach
was the utilization of an appropriate linker between 1,2,4-triazole
and benzimidazolone moieties, whereby a cyclobutyl linker displayed
superior affinity compared to a cyclohexane and phenyl linker
Probing Factor Xa ProteināLigand Interactions: Accurate Free Energy Calculations and Experimental Validations of Two Series of High-Affinity Ligands
The accurate prediction of proteināligand binding
affinity
belongs to one of the central goals in computer-based drug design.
Molecular dynamics (MD)-based free energy calculations have become
increasingly popular in this respect due to their accuracy and solid
theoretical basis. Here, we present a combined study which encompasses
experimental and computational studies on two series of factor Xa
ligands, which enclose a broad chemical space including large modifications
of the central scaffold. Using this integrated approach, we identified
several new ligands with different heterocyclic scaffolds different
from the previously identified indole-2-carboxamides that show superior
or similar affinity. Furthermore, the so far underexplored terminal
alkyne moiety proved to be a suitable non-classical bioisosteric replacement
for the higher halogenāĻ aryl interactions. With this
challenging example, we demonstrated the ability of the MD-based non-equilibrium
free energy calculation approach for guiding crucial modifications
in the lead optimization process, such as scaffold replacement and
single-site modifications at molecular interaction hot spots
Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition
Class
II phosphoinositide-3-kinases (PI3Ks) play central roles
in cell signaling, division, migration, and survival. Despite evidence
that all PI3K class II isoforms serve unique cellular functions, the
lack of isoform-selective inhibitors severely hampers the systematic
investigation of their potential relevance as pharmacological targets.
Here, we report the structural evaluation and molecular determinants
for selective PI3K-C2Ī± inhibition by a structureāactivity
relationship study based on a pteridinone scaffold, leading to the
discovery of selective PI3K-C2Ī± inhibitors called PITCOINs.
Cocrystal structures and docking experiments supported the rationalization
of the structural determinants essential for inhibitor activity and
high selectivity. Profiling of PITCOINs in a panel of more than 118
diverse kinases showed no off-target kinase inhibition. Notably, by
addressing a selectivity pocket, PITCOIN4 showed nanomolar
inhibition of PI3K-C2Ī± and >100-fold selectivity in a general
kinase panel. Our study paves the way for the development of novel
therapies for diseases related to PI3K-C2Ī± function
Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition
Class
II phosphoinositide-3-kinases (PI3Ks) play central roles
in cell signaling, division, migration, and survival. Despite evidence
that all PI3K class II isoforms serve unique cellular functions, the
lack of isoform-selective inhibitors severely hampers the systematic
investigation of their potential relevance as pharmacological targets.
Here, we report the structural evaluation and molecular determinants
for selective PI3K-C2Ī± inhibition by a structureāactivity
relationship study based on a pteridinone scaffold, leading to the
discovery of selective PI3K-C2Ī± inhibitors called PITCOINs.
Cocrystal structures and docking experiments supported the rationalization
of the structural determinants essential for inhibitor activity and
high selectivity. Profiling of PITCOINs in a panel of more than 118
diverse kinases showed no off-target kinase inhibition. Notably, by
addressing a selectivity pocket, PITCOIN4 showed nanomolar
inhibition of PI3K-C2Ī± and >100-fold selectivity in a general
kinase panel. Our study paves the way for the development of novel
therapies for diseases related to PI3K-C2Ī± function