scholarly journals Identifying Promiscuous Compounds with Activity against Different Target Classes

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4185 ◽  
Author(s):  
Christian Feldmann ◽  
Filip Miljković ◽  
Dimitar Yonchev ◽  
Jürgen Bajorath
Keyword(s):  
Small Molecules ◽  
Drug Targets ◽  
Molecular Level ◽  
Specific Interactions ◽  
Biological Screening ◽  
Systematic Analysis ◽  
X Ray ◽  
Binding Characteristics ◽  
Pharmaceutical Applications ◽  
Single Target

Compounds with multitarget activity are of high interest for polypharmacological drug discovery. Such promiscuous compounds might be active against closely related target proteins from the same family or against distantly related or unrelated targets. Compounds with activity against distinct targets are not only of interest for polypharmacology but also to better understand how small molecules might form specific interactions in different binding site environments. We have aimed to identify compounds with activity against drug targets from different classes. To these ends, a systematic analysis of public biological screening data was carried out. Care was taken to exclude compounds from further consideration that were prone to experimental artifacts and false positive activity readouts. Extensively assayed compounds were identified and found to contain molecules that were consistently inactive in all assays, active against a single target, or promiscuous. The latter included more than 1000 compounds that were active against 10 or more targets from different classes. These multiclass ligands were further analyzed and exemplary compounds were found in X-ray structures of complexes with distinct targets. Our collection of multiclass ligands should be of interest for pharmaceutical applications and further exploration of binding characteristics at the molecular level. Therefore, these highly promiscuous compounds are made publicly available.

scholarly journals Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in-vitro repurposing screen

2020 ◽  
Author(s):  
Maria Kuzikov ◽  
Elisa Costanzi ◽  
Jeanette Reinshagen ◽  
Francesca Esposito ◽  
Laura Vangeel ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Small Molecules ◽  
Drug Target ◽  
Treatment Options ◽  
Cleavage Sites ◽  
X Ray ◽  
Binding Characteristics ◽  
Main Protease ◽  
Ic50 Values

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, and have identified 62 additional compounds with IC50 values below 1 uM and profiled their selectivity towards Chymotrypsin and 3CL-Pro from the MERS virus. A subset of 8 inhibitors showed anti-cytopathic effect in a Vero-E6 cell line and the compounds thioguanosine and MG-132 were analysed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Angs., showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

Preparatory Procedures for Electron Microscopic Analysis at the Molecular Level of Resolution

1978 ◽  
Vol 36 (3) ◽  
pp. 516-520
Author(s):  
F.J. Sjostrand
Keyword(s):  
Electron Microscope ◽  
Molecular Level ◽  
Microscopic Analysis ◽  
Resolving Power ◽  
Cellular Structures ◽  
Electron Microscopic ◽  
Systematic Analysis ◽  
Technical Developments ◽  
Thin Sectioning ◽  
Obvious Reason

In the 1940's and 1950's electron microscopy conferences were attended with everybody interested in learning about the latest technical developments for one very obvious reason. There was the electron microscope with its outstanding performance but nobody could make very much use of it because we were lacking proper techniques to prepare biological specimens. The development of the thin sectioning technique with its perfectioning in 1952 changed the situation and systematic analysis of the structure of cells could now be pursued. Since then electron microscopists have in general become satisfied with the level of resolution at which cellular structures can be analyzed when applying this technique. There has been little interest in trying to push the limit of resolution closer to that determined by the resolving power of the electron microscope.

RNA polymerase: Preparation and structural analysis of helical polymers

1984 ◽  
Vol 42 ◽  
pp. 152-153
Author(s):  
E. Loren Buhle ◽  
Pamela Rew ◽  
Ueli Aebi
Keyword(s):  
Structural Analysis ◽  
Rna Polymerase ◽  
Molecular Level ◽  
X Ray Diffraction ◽  
Helical Polymers ◽  
X Ray ◽  
E Coli ◽  
The Past ◽  
Ordered Arrays ◽  
Low Ionic Strength

While DNA-dependent RNA polymerase represents one of the key enzymes involved in transcription and ultimately in gene expression in procaryotic and eucaryotic cells, little progress has been made towards elucidation of its 3-D structure at the molecular level over the past few years. This is mainly because to date no 3-D crystals suitable for X-ray diffraction analysis have been obtained with this rather large (MW ~500 kd) multi-subunit (α2ββ'ζ). As an alternative, we have been trying to form ordered arrays of RNA polymerase from E. coli suitable for structural analysis in the electron microscope combined with image processing. Here we report about helical polymers induced from holoenzyme (α2ββ'ζ) at low ionic strength with 5-7 mM MnCl2 (see Fig. 1a). The presence of the ζ-subunit (MW 86 kd) is required to form these polymers, since the core enzyme (α2ββ') does fail to assemble into such structures under these conditions.

scholarly journals Network Analysis Identifies Drug Targets and Small Molecules to Modulate Apoptosis Resistant Cancers

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 851
Author(s):  
Samreen Fathima ◽  
Swati Sinha ◽  
Sainitin Donakonda
Keyword(s):  
Cell Death ◽  
Small Molecules ◽  
Drug Targets ◽  
Apoptotic Cell ◽  
Colon Adenocarcinoma ◽  
Interaction Networks ◽  
Small Cell Lung ◽  
Protein Protein Interaction ◽  
Cell Death Genes ◽  
Death Genes

Programed cell death or apoptosis fails to induce cell death in many recalcitrant cancers. Thus, there is an emerging need to activate the alternate cell death pathways in such cancers. In this study, we analyzed the apoptosis-resistant colon adenocarcinoma, glioblastoma multiforme, and small cell lung cancers transcriptome profiles. We extracted clusters of non-apoptotic cell death genes from each cancer to understand functional networks affected by these genes and their role in the induction of cell death when apoptosis fails. We identified transcription factors regulating cell death genes and protein–protein interaction networks to understand their role in regulating cell death mechanisms. Topological analysis of networks yielded FANCD2 (ferroptosis, negative regulator, down), NCOA4 (ferroptosis, up), IKBKB (alkaliptosis, down), and RHOA (entotic cell death, down) as potential drug targets in colon adenocarcinoma, glioblastoma multiforme, small cell lung cancer phenotypes respectively. We also assessed the miRNA association with the drug targets. We identified tumor growth-related interacting partners based on the pathway information of drug-target interaction networks. The protein–protein interaction binding site between the drug targets and their interacting proteins provided an opportunity to identify small molecules that can modulate the activity of functional cell death interactions in each cancer. Overall, our systematic screening of non-apoptotic cell death-related genes uncovered targets helpful for cancer therapy.

scholarly journals Physical and chemical imaging of adhesive interfaces with soft X-rays

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Hiroyuki Yamane ◽  
Masaki Oura ◽  
Osamu Takahashi ◽  
Tomoko Ishihara ◽  
Noriko Yamazaki ◽  
...  
Keyword(s):  
Molecular Level ◽  
Covalent Bond ◽  
Chemical Imaging ◽  
Diglycidyl Ether ◽  
X Rays ◽  
X Ray ◽  
Covalent Bond Formation ◽  
Chemical States ◽  
The Individual ◽  
Physical And Chemical

AbstractAdhesion is an interfacial phenomenon that is critical for assembling carbon structural composites for next-generation aircraft and automobiles. However, there is limited understanding of adhesion on the molecular level because of the difficulty in revealing the individual bonding factors. Here, using soft X-ray spectromicroscopy we show the physical and chemical states of an adhesive interface composed of a thermosetting polymer of 4,4’-diaminodiphenylsulfone-cured bisphenol A diglycidyl ether adhered to a thermoplastic polymer of plasma-treated polyetheretherketone. We observe multiscale phenomena in the adhesion mechanisms, including sub-mm complex interface structure, sub-μm distribution of the functional groups, and molecular-level covalent-bond formation. These results provide a benchmark for further research to examine how physical and chemical states correlate with adhesion, and demonstrate that soft X-ray imaging is a promising approach for visualizing the physical and chemical states at adhesive interfaces from the sub-mm level to the molecular level.

scholarly journals Fine-tuning of a generative neural network for designing multi-target compounds

2021 ◽  
Author(s):  
Thomas Blaschke ◽  
Jürgen Bajorath
Keyword(s):  
Neural Network ◽  
Small Molecules ◽  
De Novo ◽  
Pharmaceutical Research ◽  
Generative Models ◽  
Fine Tuning ◽  
Data Sets ◽  
Single Target ◽  
Fine Tune ◽  
Target Activity

AbstractExploring the origin of multi-target activity of small molecules and designing new multi-target compounds are highly topical issues in pharmaceutical research. We have investigated the ability of a generative neural network to create multi-target compounds. Data sets of experimentally confirmed multi-target, single-target, and consistently inactive compounds were extracted from public screening data considering positive and negative assay results. These data sets were used to fine-tune the REINVENT generative model via transfer learning to systematically recognize multi-target compounds, distinguish them from single-target or inactive compounds, and construct new multi-target compounds. During fine-tuning, the model showed a clear tendency to increasingly generate multi-target compounds and structural analogs. Our findings indicate that generative models can be adopted for de novo multi-target compound design.

scholarly journals Synthesis, characterization and modeling of self-assembled porphyrin nanorods

2019 ◽  
Vol 23 (11n12) ◽  
pp. 1346-1354 ◽  
Author(s):  
Danielle Laurencin ◽  
Pascal G. Yot ◽  
Christel Gervais ◽  
Yannick Guari ◽  
Sébastien Clément ◽  
...  
Keyword(s):  
Solid State ◽  
Nmr Spectroscopy ◽  
Dft Calculations ◽  
Powder Diffraction ◽  
Solid State Nmr ◽  
Molecular Level ◽  
Ion Association ◽  
Free Base ◽  
X Ray ◽  
Solid State Nmr Spectroscopy

Porphyrin nanorods were prepared by ion-association between free-base meso 5,10,15,20-tetrakis-(4-[Formula: see text]-methylpyridinium)porphyrin cations and tetraphenylborate anions. The nanorods have variable lengths (up to a few micrometers long) and diameters ([Formula: see text]50–500 nm). Their structure at the molecular level was elucidated by combining multinuclear solid state NMR spectroscopy, synchrotron X-ray powder diffraction and DFT calculations.

scholarly journals A new one-pot three-component synthesis of 4-aryl-6-cycloamino-1,3,5-triazin-2-amines under microwave irradiation

Synthesis ◽  
2021 ◽  
Author(s):  
Muhammad Syafiq Bin Shahari ◽  
Ahmad Junaid ◽  
Edward R. T. Tiekink ◽  
Anton V. Dolzhenko
Keyword(s):  
Microwave Irradiation ◽  
Aromatic Aldehydes ◽  
Antileukemic Activity ◽  
One Pot ◽  
Biological Screening ◽  
X Ray ◽  
X Ray Crystallography ◽  
Cyclic Amines ◽  
Three Component Reaction ◽  
Fast Synthesis

A new method for the fast synthesis of diverse 4-aryl-6-cycloamino-1,3,5-triazin-2-amines was developed. The synthesis is performed under microwave irradiation in a one-pot manner from cyanoguanidine, aromatic aldehydes, and cyclic amines. Their three-component reaction in the presence of hydrochloric acid produced dihydrotriazines, which were then converted (without isolation) to the targeted compounds via aromatic dehydrogenation in the presence of alkali. The reaction tolerated various aromatic aldehydes (including heterocyclic) and cyclic amines. Crystal structures of two representative 4-aryl-6-morpholino-1,3,5-triazin-2-amines were established by X-ray crystallography. The results of preliminary biological screening identified potent antileukemic activity for 6-(3,4-dihydroisoquinolin-2(1<i>H</i>)-yl)-4-phenyl-1,3,5-triazin-2-amine.

Adsorption Capacity of Y Zeolite Using Organic Solvents such as Adsorbates

2014 ◽  
Vol 805 ◽  
pp. 641-645
Author(s):  
Ana Paula Araújo ◽  
Aline Cadigena Lima Patrício ◽  
Anna Karoline Freires de Sousa ◽  
Mariaugusta Ferreira Mota ◽  
Meiry Glaúcia Freire Rodrigues
Keyword(s):  
Small Molecules ◽  
Adsorption Capacity ◽  
Selective Adsorption ◽  
X Ray Diffraction ◽  
Y Zeolite ◽  
High Adsorption ◽  
X Ray ◽  
Low Concentrations ◽  
Adsorption Of Nitrogen ◽  
Type Zeolite

The zeolites differ from traditional adsorbents for selective adsorption of small molecules, the high adsorption capacity at low concentrations and affinity for organic compounds and unsaturated polar molecules. In this work a Y-type zeolite was synthesized, characterized by x-ray diffraction, scanning electron microscopy and adsorption of nitrogen and subjected to test adsorption capacity where it was found that the Y zeolite has the potential adsorption capacity compared to other materials being studied and marketed.

Sign in / Sign up

Export Citation Format

Share Document