9 research outputs found
A novel series of positive modulators of the AMPA receptor : discovery and structure based hit-to-lead studies
Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor
Structure based evolution of a novel series of positive modulators of the AMPA receptor
Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotyope with a promising overall profile, exemplified by
<em>De novo</em> design of protein kinase inhibitors by<em> in silico</em> identification of hinge region-binding fragments
[Image: see text] Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible with hinge-region binding, and docked into a panel of protein kinases. Fragments with a high consensus score were subsequently short-listed for synthesis. Application of this strategy led to a number of core fragments with no previously reported activity against kinases. Small libraries around the core fragments were synthesized, and representative compounds were tested against a large panel of protein kinases and subjected to co-crystallization experiments. Each of the tested compounds was active against at least one kinase, but not all kinases in the panel were inhibited. A number of compounds showed high ligand efficiencies for therapeutically relevant kinases; among them were MAPKAP-K3, SRPK1, SGK1, TAK1, and GCK for which only few inhibitors are reported in the literature
<i>De Novo</i> Design of Protein Kinase Inhibitors by <i>in Silico</i> Identification of Hinge Region-Binding Fragments
Protein kinases constitute an attractive
family of enzyme targets
with high relevance to cell and disease biology. Small molecule inhibitors
are powerful tools to dissect and elucidate the function of kinases
in chemical biology research and to serve as potential starting points
for drug discovery. However, the discovery and development of novel
inhibitors remains challenging. Here, we describe a structure-based <i>de novo</i> design approach that generates novel, hinge-binding
fragments that are synthetically feasible and can be elaborated to
small molecule libraries. Starting from commercially available compounds,
core fragments were extracted, filtered for pharmacophoric properties
compatible with hinge-region binding, and docked into a panel of protein
kinases. Fragments with a high consensus score were subsequently short-listed
for synthesis. Application of this strategy led to a number of core
fragments with no previously reported activity against kinases. Small
libraries around the core fragments were synthesized, and representative
compounds were tested against a large panel of protein kinases and
subjected to co-crystallization experiments. Each of the tested compounds
was active against at least one kinase, but not all kinases in the
panel were inhibited. A number of compounds showed high ligand efficiencies
for therapeutically relevant kinases; among them were MAPKAP-K3, SRPK1,
SGK1, TAK1, and GCK for which only few inhibitors are reported in
the literature
A novel series of positive modulators of the AMPA receptor : structure-based lead optimization
Starting from lead compound 1, we demonstrate how x-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity
Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist
High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist
Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity
There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for Mycobacterium tuberculosis growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC < 1 μM) and in vitro ADMET profiles.</p