scholarly journals Extending the small molecule similarity principle to all levels of biology

2019 ◽  
Author(s):  
Miquel Duran-Frigola ◽  
Eduardo Pauls ◽  
Oriol Guitart-Pla ◽  
Martino Bertoni ◽  
Víctor Alcalde ◽  
...  

AbstractWe present the Chemical Checker (CC), a resource that provides processed, harmonized and integrated bioactivity data on 800,000 small molecules. The CC divides data into five levels of increasing complexity, ranging from the chemical properties of compounds to their clinical outcomes. In between, it considers targets, off-targets, perturbed biological networks and several cell-based assays such as gene expression, growth inhibition and morphological profilings. In the CC, bioactivity data are expressed in a vector format, which naturally extends the notion of chemical similarity between compounds to similarities between bioactivity signatures of different kinds. We show how CC signatures can boost the performance of drug discovery tasks that typically capitalize on chemical descriptors, including target identification and library characterization. Moreover, we demonstrate and experimentally validate that CC signatures can be used to reverse and mimic biological signatures of disease models and genetic perturbations, options that are otherwise impossible using chemical information alone.

2021 ◽  
Author(s):  
David Dayanidhi Paul Elisa Sundar ◽  
Vaidyanathan Ganesan

Studies on the binding interaction of small molecules and nucleic acids have been explored for their biological applications. With excellent photophysical/chemical properties, numerous metal complexes have been studied as structural...


2017 ◽  
Author(s):  
Neel S. Madhukar ◽  
Prashant K. Khade ◽  
Linda Huang ◽  
Kaitlyn Gayvert ◽  
Giuseppe Galletti ◽  
...  

AbstractDrug target identification is one of the most important aspects of pre-clinical development yet it is also among the most complex, labor-intensive, and costly. This represents a major issue, as lack of proper target identification can be detrimental in determining the clinical application of a bioactive small molecule. To improve target identification, we developed BANDIT, a novel paradigm that integrates multiple data types within a Bayesian machine-learning framework to predict the targets and mechanisms for small molecules with unprecedented accuracy and versatility. Using only public data BANDIT achieved an accuracy of approximately 90% over 2000 different small molecules – substantially better than any other published target identification platform. We applied BANDIT to a library of small molecules with no known targets and generated ∼4,000 novel molecule-target predictions. From this set we identified and experimentally validated a set of novel microtubule inhibitors, including three with activity on cancer cells resistant to clinically used anti-microtubule therapies. We next applied BANDIT to ONC201 – an active anti- cancer small molecule in clinical development – whose target has remained elusive since its discovery in 2009. BANDIT identified dopamine receptor 2 as the unexpected target of ONC201, a prediction that we experimentally validated. Not only does this open the door for clinical trials focused on target-based selection of patient populations, but it also represents a novel way to target GPCRs in cancer. Additionally, BANDIT identified previously undocumented connections between approved drugs with disparate indications, shedding light onto previously unexplained clinical observations and suggesting new uses of marketed drugs. Overall, BANDIT represents an efficient and highly accurate platform that can be used as a resource to accelerate drug discovery and direct the clinical application of small molecule therapeutics with improved precision.


1999 ◽  
Vol 599 ◽  
Author(s):  
I. A. Belío-Reyes ◽  
L. F. JimÉNez-García ◽  
J. Reyes-Gasga

AbstractThe aim of the present study is to obtain structural and chemical information about nucleation and growth of dental enamel as a function of location in secretory mouse foetus enamel. Then enamel tissues were obtained from 19-days-mouse foetus. TEM images show that enamel crystallites had the well-documented thin ribbons, or needles. They were found in the outermost zone in the vicinity of ameloblasts. Chemical analysis by EDS showed that, besides the elements of hydroxyapatite, Na, Cl, Al and Mg are presents from the beginning of enamel mineralization. All of these elements will play an important role on the physics and chemical properties in mature enamel.


1937 ◽  
Vol 66 (3) ◽  
pp. 353-366 ◽  
Author(s):  
Albert Claude

1. The injection of leech extracts into the skin increases its permeability, as shown both by the spread of fluid and of foreign particles through the dermis. The spread is followed some hours after the injection by more or less edema of the subcutaneous tissue. 2. A preliminary study of the chemical properties of the leech spreading factor indicates a similarity with the spreading factor prepared from testicle. 3. Attempts to separate the leech spreading and anticoagulating factors showed that the two have practically the same distribution in the leech body, extracts from the separated head being the most active. 4. It is undetermined whether two distinct factors are responsible for the spreading and anticoagulating properties of leech extracts. A chemical similarity is suggested by the fact that agents which affect the activity of one factor have a parallel effect on the other. 5. The mechanism of the spread produced by leech extracts and by other spreading agents is discussed.


1981 ◽  
Vol 6 ◽  
Author(s):  
Paul G. Huray ◽  
M. T. Spaar ◽  
S. E. Nave ◽  
J. M. Legan ◽  
L. A. Boatner ◽  
...  

The electronic charge states and site symmetries of the radioactive ions incorporated in nuclear waste forms are of considerable importance in determining the physical and chemical properties of these materials. An in situ characterization of these ions is, unfortunately, often difficult – especially when a mixture of charge states and local crystal symmetries exist. The application of Mbssbauer spectroscopy represents a powerful technique for obtaining solid state chemical information.


Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5702
Author(s):  
Quentin T. L. Pasquer ◽  
Ioannis A. Tsakoumagkos ◽  
Sascha Hoogendoorn

Biologically active small molecules have a central role in drug development, and as chemical probes and tool compounds to perturb and elucidate biological processes. Small molecules can be rationally designed for a given target, or a library of molecules can be screened against a target or phenotype of interest. Especially in the case of phenotypic screening approaches, a major challenge is to translate the compound-induced phenotype into a well-defined cellular target and mode of action of the hit compound. There is no “one size fits all” approach, and recent years have seen an increase in available target deconvolution strategies, rooted in organic chemistry, proteomics, and genetics. This review provides an overview of advances in target identification and mechanism of action studies, describes the strengths and weaknesses of the different approaches, and illustrates the need for chemical biologists to integrate and expand the existing tools to increase the probability of evolving screen hits to robust chemical probes.


2015 ◽  
Vol 15 (6) ◽  
pp. 2985-3005 ◽  
Author(s):  
J.-E. Petit ◽  
O. Favez ◽  
J. Sciare ◽  
V. Crenn ◽  
R. Sarda-Estève ◽  
...  

Abstract. Aerosol mass spectrometer (AMS) measurements have been successfully used towards a better understanding of non-refractory submicron (PM1) aerosol chemical properties based on short-term campaigns. The recently developed Aerosol Chemical Speciation Monitor (ACSM) has been designed to deliver quite similar artifact-free chemical information but for low cost, and to perform robust monitoring over long-term periods. When deployed in parallel with real-time black carbon (BC) measurements, the combined data set allows for a quasi-comprehensive description of the whole PM1 fraction in near real time. Here we present 2-year long ACSM and BC data sets, between mid-2011 and mid-2013, obtained at the French atmospheric SIRTA supersite that is representative of background PM levels of the region of Paris. This large data set shows intense and time-limited (a few hours) pollution events observed during wintertime in the region of Paris, pointing to local carbonaceous emissions (mainly combustion sources). A non-parametric wind regression analysis was performed on this 2-year data set for the major PM1 constituents (organic matter, nitrate, sulfate and source apportioned BC) and ammonia in order to better refine their geographical origins and assess local/regional/advected contributions whose information is mandatory for efficient mitigation strategies. While ammonium sulfate typically shows a clear advected pattern, ammonium nitrate partially displays a similar feature, but, less expectedly, it also exhibits a significant contribution of regional and local emissions. The contribution of regional background organic aerosols (OA) is significant in spring and summer, while a more pronounced local origin is evidenced during wintertime, whose pattern is also observed for BC originating from domestic wood burning. Using time-resolved ACSM and BC information, seasonally differentiated weekly diurnal profiles of these constituents were investigated and helped to identify the main parameters controlling their temporal variations (sources, meteorological parameters). Finally, a careful investigation of all the major pollution episodes observed over the region of Paris between 2011 and 2013 was performed and classified in terms of chemical composition and the BC-to-sulfate ratio used here as a proxy of the local/regional/advected contribution of PM. In conclusion, these first 2-year quality-controlled measurements of ACSM clearly demonstrate their great potential to monitor on a long-term basis aerosol sources and their geographical origin and provide strategic information in near real time during pollution episodes. They also support the capacity of the ACSM to be proposed as a robust and credible alternative to filter-based sampling techniques for long-term monitoring strategies.


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