13 research outputs found
Lead optimization for new antimalarials and Successful lead identification for metalloproteinases: A Fragment-based approach Using Virtual Screening
Lead optimization for new antimalarials and Successful lead identification
for metalloproteinases: A Fragment-based approach Using Virtual Screening
Computer-aided drug design is an essential part of the modern medicinal
chemistry, and has led to the acceleration of many projects. The herein
described thesis presents examples for its application in the field of lead
optimization and lead identification for three metalloproteins.
DOXP-reductoisomerase (DXR) is a key enzyme of the mevalonate independent
isoprenoid biosynthesis. Structure-activity relationships for 43 DXR
inhibitors are established, derived from protein-based docking, ligand-based
3D QSAR and a combination of both approaches as realized by AFMoC. As part
of an effort to optimize the properties of the established inhibitor
Fosmidomycin, analogues have been synthesized and tested to gain further
insights into the primary determinants of structural affinity.
Unfortunately, these structures still leave the active Fosmidomycin
conformation and detailed reaction mechanism undetermined. This fact,
together with the small inhibitor data set provides a major challenge for
presently available docking programs and 3D QSAR tools. Using the recently
developed protein tailored scoring protocol AFMoC precise prediction of
binding affinities for related ligands as well as the capability to estimate
the affinities of structurally distinct inhibitors has been achieved.
Farnesyltransferase is a zinc-metallo enzyme that catalyzes the
posttranslational modification of numerous proteins involved in
intracellular signal transduction. The development of farnesyltransferase
inhibitors is directed towards the so-called non-thiol inhibitors because of
adverse drug effects connected to free thiols. A first step on the way to
non-thiol farnesyltransferase inhibitors was the development of an
CAAX-benzophenone peptidomimetic based on a pharmacophore model. On its
basis bisubstrate analogues were developed as one class of non-thiol
farnesyltransferase inhibitors. In further studies two aryl binding and two
distinct specificity sites were postulated. Flexible docking of model
compounds was applied to investigate the sub-pockets and design highly
active non-thiol farnesyltransferase inhibitor. In addition to affinity,
special attention was paid towards in vivo activity and species specificity.
The second part of this thesis describes a possible strategy for
computer-aided lead discovery. Assembling a complex ligand from simple
fragments has recently been introduced as an alternative to traditional HTS.
While frequently applied experimentally, only a few examples are known for
computational fragment-based approaches. Mostly, computational tools are
applied to compile the libraries and to finally assess the assembled
ligands. Using the metalloproteinase thermolysin (TLN) as a model target, a
computational fragment-based screening protocol has been established.
Starting with a data set of commercially available chemical compounds, a
fragment library has been compiled considering (1) fragment likeness and (2)
similarity to known drugs. The library is screened for target specificity,
resulting in 112 fragments to target the zinc binding area and 75 fragments
targeting the hydrophobic specificity pocket of the enzyme. After analyzing
the performance of multiple docking programs and scoring functions forand the most 14 candidates are selected for further analysis. Soaking
experiments were performed for reference fragment to derive a general
applicable crystallization protocol for TLN and subsequently for new
protein-fragment complex structures. 3-Methylsaspirin could be determined to
bind to TLN. Additional studies addressed a retrospective performance
analysis of the applied scoring functions and modification on the screening
hit. Curios about the differences of aspirin and 3-methylaspirin,
3-chloroaspirin has been synthesized and affinities could be determined to
be 2.42 mM; 1.73 mM und 522 ÎŒM respectively.
The results of the thesis show, that computer aided drug design approaches
could successfully support projects in lead optimization and lead
identification.
fragments in general, the fragments derived from the screening are docke
Lead optimization for new antimalarials and Successful lead identification for metalloproteinases: A Fragment-based approach Using Virtual Screening
Lead optimization for new antimalarials and Successful lead identification
for metalloproteinases: A Fragment-based approach Using Virtual Screening
Computer-aided drug design is an essential part of the modern medicinal
chemistry, and has led to the acceleration of many projects. The herein
described thesis presents examples for its application in the field of lead
optimization and lead identification for three metalloproteins.
DOXP-reductoisomerase (DXR) is a key enzyme of the mevalonate independent
isoprenoid biosynthesis. Structure-activity relationships for 43 DXR
inhibitors are established, derived from protein-based docking, ligand-based
3D QSAR and a combination of both approaches as realized by AFMoC. As part
of an effort to optimize the properties of the established inhibitor
Fosmidomycin, analogues have been synthesized and tested to gain further
insights into the primary determinants of structural affinity.
Unfortunately, these structures still leave the active Fosmidomycin
conformation and detailed reaction mechanism undetermined. This fact,
together with the small inhibitor data set provides a major challenge for
presently available docking programs and 3D QSAR tools. Using the recently
developed protein tailored scoring protocol AFMoC precise prediction of
binding affinities for related ligands as well as the capability to estimate
the affinities of structurally distinct inhibitors has been achieved.
Farnesyltransferase is a zinc-metallo enzyme that catalyzes the
posttranslational modification of numerous proteins involved in
intracellular signal transduction. The development of farnesyltransferase
inhibitors is directed towards the so-called non-thiol inhibitors because of
adverse drug effects connected to free thiols. A first step on the way to
non-thiol farnesyltransferase inhibitors was the development of an
CAAX-benzophenone peptidomimetic based on a pharmacophore model. On its
basis bisubstrate analogues were developed as one class of non-thiol
farnesyltransferase inhibitors. In further studies two aryl binding and two
distinct specificity sites were postulated. Flexible docking of model
compounds was applied to investigate the sub-pockets and design highly
active non-thiol farnesyltransferase inhibitor. In addition to affinity,
special attention was paid towards in vivo activity and species specificity.
The second part of this thesis describes a possible strategy for
computer-aided lead discovery. Assembling a complex ligand from simple
fragments has recently been introduced as an alternative to traditional HTS.
While frequently applied experimentally, only a few examples are known for
computational fragment-based approaches. Mostly, computational tools are
applied to compile the libraries and to finally assess the assembled
ligands. Using the metalloproteinase thermolysin (TLN) as a model target, a
computational fragment-based screening protocol has been established.
Starting with a data set of commercially available chemical compounds, a
fragment library has been compiled considering (1) fragment likeness and (2)
similarity to known drugs. The library is screened for target specificity,
resulting in 112 fragments to target the zinc binding area and 75 fragments
targeting the hydrophobic specificity pocket of the enzyme. After analyzing
the performance of multiple docking programs and scoring functions forand the most 14 candidates are selected for further analysis. Soaking
experiments were performed for reference fragment to derive a general
applicable crystallization protocol for TLN and subsequently for new
protein-fragment complex structures. 3-Methylsaspirin could be determined to
bind to TLN. Additional studies addressed a retrospective performance
analysis of the applied scoring functions and modification on the screening
hit. Curios about the differences of aspirin and 3-methylaspirin,
3-chloroaspirin has been synthesized and affinities could be determined to
be 2.42 mM; 1.73 mM und 522 ÎŒM respectively.
The results of the thesis show, that computer aided drug design approaches
could successfully support projects in lead optimization and lead
identification.
fragments in general, the fragments derived from the screening are docke
The microtubule stabilizer patupilone (epothilone B) is a potent radiosensitizer in medulloblastoma cells
Concurrent radiochemotherapy for medulloblastoma includes the microtubule disrupting agent vincristine; however, vincristine alone or as part of a combined treatment regimen is highly toxic. A major goal is therefore to replace vincristine with novel potent chemotherapeutic agents-in particular, with microtubule stabilizing and destabilizing compounds-with a larger therapeutic window. Here, we investigated the antiproliferative, cytotoxic and radiosensitizing effect of patupilone (epothilone B [EPO906]), a novel, non-taxane-related and nonneurotoxic microtubule-stabilizing agent in human medulloblastoma cell lines. The antiproliferative and cytotoxic effects of patupilone alone and in combination with ionizing radiation was determined in the 3 representative human medulloblastoma cell lines D341Med, D425Med, and DAOY. Patupilone alone effectively reduced the proliferative activity and clonogenicity of all medulloblastoma cell lines tested at picomolar concentrations (50-200 pM) and resulted in an at least additive anticlonogenic effect in combination with clinically relevant doses of ionizing radiation (2 or 5 Gy). Cell-cycle analysis revealed a sequential G2-M arrest and sub-G1 accumulation in a dose- and treatment-dependent manner after exposure to patupilone. In tumor xenografts derived from D425Med cells, a minimal treatment regimen with patupilone and fractionated irradiation (1 Ă 2 mg/kg plus 3 Ă 3 Gy) resulted in an extended tumor growth delay for the 2 single treatment modalities alone and a supra-additive treatment response for the combined treatment modality, with complete tumor regressions. These results demonstrate the potent efficacy of patupilone against medulloblastoma cell lines and indicate that patupilone represents a promising candidate to replace vincristine as part of a combined treatment strategy with ionizing radiation
The DESI experiment part I: science, targeting, and survey design
DESI (Dark Energy Spectroscopic Instrument) is a Stage IV ground-based dark energy experiment that will study baryon acoustic oscillations (BAO) and the growth of structure through redshift-space distortions with a wide-area galaxy and quasar redshift survey. To trace the underlying dark matter distribution, spectroscopic targets will be selected in four classes from imaging data. We will measure luminous red galaxies up to . To probe the Universe out to even higher redshift, DESI will target bright [O II] emission line galaxies up to . Quasars will be targeted both as direct tracers of the underlying dark matter distribution and, at higher redshifts (), for the Ly- forest absorption features in their spectra, which will be used to trace the distribution of neutral hydrogen. When moonlight prevents efficient observations of the faint targets of the baseline survey, DESI will conduct a magnitude-limited Bright Galaxy Survey comprising approximately 10 million galaxies with a median . In total, more than 30 million galaxy and quasar redshifts will be obtained to measure the BAO feature and determine the matter power spectrum, including redshift space distortions