15 research outputs found
Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of repurposing drug libraries containing 5953 individual compounds against the SARS-CoV-2 main protease (Mpro), which is a potent drug target as it is essential for the virus replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. Interestingly, two compounds bind outside the active site to the native dimer interface in close proximity to the S1 binding pocket. Another compound binds in a cleft between the catalytic and dimerization domain of Mpro. Neither binding site is related to the enzymatic active site and both represent attractive targets for drug development against SARS-CoV-2. This X-ray screening approach thus has the potential to help deliver an approved drug on an accelerated time-scale for this and future pandemics
X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M^(pro)), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M^(pro). In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2
Structural Elucidation of α-Cyclodextrin-Succinic Acid Pseudo Dodecahydrate: Expanding the Packing Types of α-Cyclodextrin Inclusion Complexes
This paper reports a new packing type of -cyclodextrin inclusion complexes, obtained
here with succinic acid under low-temperature crystallization conditions. The structure of the 1:1
complex is characterized by heavy disorder of the guest, the solvent, and part of the host. The
crystal packing belongs to the known channel-type structure; the basic structural unit is composed
of cyclodextrin trimers, as opposed to the known isolated molecular or dimeric constructs, packed
along the c-axis. Each trimer is made of crystallographically independent molecules assembled in
a stacked vase-like cluster. A multi-temperature single-crystal X-ray diffraction analysis reveals the
presence of dynamic disorder
Structural Behavior of Long-Chain Imidazolium-Based Ionic Liquid [C<sub>10</sub>mim]Cl–Water Mixtures
The
structural behavior of long-chain imidazolium-based ionic liquid
[C<sub>10</sub>mim]ÂCl–water mixtures has been investigated
in detail by low-temperature and high-pressure crystallization methods,
and the solid forms have been fully characterized by single-crystal
X-ray diffraction. Form I, a monohydrate, crystallizes from solutions
containing 6–8% (w/w) water; its structure exhibits bilayers,
in which the cations alternate from layer to layer to create hydrophobic
and hydrophilic regions. Form II, which is a <i>Z</i>′
> 1 structure, incorporates a variable amount of water content
(from
pseudo-hemihydrate to pseudo-monohydrate) depending on the sample
treatment and environment; this form crystallizes from solutions containing
< ca. 6% (w/w) water and exhibits a double bilayered structure
characterized by ordered and disordered regions. Forms I and II have
been obtained at both low-temperature and high-pressure conditions.
Form III is a trihydrate that has been exclusively obtained under
high-pressure conditions above 0.55 GPa from solutions containing >80%
(w/w) water. This structure is closely related to that of form I.
While homeotypic and isotypic structures of forms I and II have been
previously reported, form III represents, to the best of our knowledge,
the only example of a highly hydrated long-chain imidazolium-based
ionic liquid isolated in the solid state. The formation of mesophases
in the title compound has also been investigated by polarized optical
microscopy, and the results were correlated with previous liquid-crystal
studies on related compounds
CCDC 909175: Experimental Crystal Structure Determination
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures
CCDC 909172: Experimental Crystal Structure Determination
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures
CCDC 909174: Experimental Crystal Structure Determination
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures
CCDC 909173: Experimental Crystal Structure Determination
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures
CCDC 909171: Experimental Crystal Structure Determination
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures