Dataset Information

Real-Time Biological Annotation of Synthetic Compounds.

ABSTRACT: Organic chemists are able to synthesize molecules in greater number and chemical complexity than ever before. Yet, a majority of these compounds go untested in biological systems, and those that do are often tested long after the chemist can incorporate the results into synthetic planning. We propose the use of high-dimensional "multiplex" assays, which are capable of measuring thousands of cellular features in one experiment, to annotate rapidly and inexpensively the biological activities of newly synthesized compounds. This readily accessible and inexpensive "real-time" profiling method can be used in a prospective manner to facilitate, for example, the efficient construction of performance-diverse small-molecule libraries that are enriched in bioactives. Here, we demonstrate this concept by synthesizing ten triads of constitutionally isomeric compounds via complexity-generating photochemical and thermal rearrangements and measuring compound-induced changes in cellular morphology via an imaging-based "cell painting" assay. Our results indicate that real-time biological annotation can inform optimization efforts and library syntheses by illuminating trends relating to biological activity that would be difficult to predict if only chemical structure were considered. We anticipate that probe and drug discovery will benefit from the use of optimization efforts and libraries that implement this approach.

SUBMITTER: Gerry CJ

PROVIDER: S-EPMC4976700 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

Real-Time Biological Annotation of Synthetic Compounds.

Gerry Christopher J CJ Hua Bruce K BK Wawer Mathias J MJ Knowles Jonathan P JP Nelson Shawn D SD Verho Oscar O Dandapani Sivaraman S Wagner Bridget K BK Clemons Paul A PA Booker-Milburn Kevin I KI Boskovic Zarko V ZV Schreiber Stuart L SL

Journal of the American Chemical Society 20160711 28

Organic chemists are able to synthesize molecules in greater number and chemical complexity than ever before. Yet, a majority of these compounds go untested in biological systems, and those that do are often tested long after the chemist can incorporate the results into synthetic planning. We propose the use of high-dimensional "multiplex" assays, which are capable of measuring thousands of cellular features in one experiment, to annotate rapidly and inexpensively the biological activities of ne ...[more]

PMID: 27398798

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Project description:Diffusion exchange spectroscopy (DEXSY) provides a means to isolate the signal attenuation associated with exchange from other sources of signal loss. With the total diffusion weighting b1+b2=bs held constant, DEXSY signals acquired with b1=0 or b2=0 have no exchange weighting, while a DEXSY signal acquired with b1=b2 has maximal exchange weighting. The exchange rate can be estimated by fitting a diffusion exchange model to signals acquired with variable mixing times. Conventionally, acquired signals are normalized by a signal with b1=0 and b2=0 to remove the decay due to spin-lattice relaxation. Instead, division by a signal with equal bs but b1=0 or b2=0 reduces spin-lattice relaxation weighting of the apparent exchange rate (AXR). Furthermore, apparent diffusion-weighted R1 relaxation rates can be estimated from non-exchange-weighted DEXSY signals. Estimated R1 values are utilized to remove signal decay due to spin-lattice relaxation from exchange-weighted signals, permitting a more precise estimate of AXR with less data. Data reduction methods are proposed and tested with regards to statistical accuracy and precision of AXR estimates on simulated and experimental data. Simulations show that the methods are capable of accurately measuring the ground-truth exchange rate. The methods remain accurate even when the assumption that DEXSY signals attenuate with b is violated, as occurs for restricted diffusion. Experimental data was collected from fixed neonatal mouse spinal cord samples at 25 and 7°C using the strong static magnetic field gradient produced by a single-sided permanent magnet (i.e., an NMR MOUSE). The most rapid method for exchange measurements requires only five data points (an 80 s experiment as implemented) and achieves a similar level of accuracy and precision to the baseline method using 44 data points. This represents a significant improvement in acquisition speed, overcoming a barrier which has limited the use of DEXSY on living specimen.

Dataset Information

Real-Time Biological Annotation of Synthetic Compounds.

Publications

Real-Time Biological Annotation of Synthetic Compounds.

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