Posts classified under: Aside

Towards an automatic structure elucidation process in various chemical workflows by LC-HRMS and NMR data analysis

254th ACS National Meeting, Washington DC (United States of America) 20 August 2017 

Abstract

MassChemSite (Molecular Discovery, Ltd. UK) is a novel vendor agnostic software which automatizes the peak finding and structure elucidation from LC-HRMS analytical data obtained from chemical reaction samples, speeding up this task. MassChemSite can identify the reactants and products of a sample based on MS/MSMS information and the chemical reactions under consideration.

Two new features were recently added to MassChemSite: the first one is a method applied to elucidate unknown structures (i.e., when the m/z found is not obtained by the combination of reactions used as input) from unassigned LC-HRMS peaks. First, m/z values from the input MSMS are queried in a database of fragments of compounds (built from user compounds, or previously built and provided). Then, a set of candidate compounds is built by rational combination of the fragments found in the database.

Finally, all the candidates are fragmented and compared with the peaks of the input MSMS spectra. The second feature is an algorithm that uses different NMR acquisition methodologies to discriminate between multiple solutions, for example when LC-HRMS analysis cannot provide a unique structural solution, or to further refine the results of the unknown structure elucidation method. Chemists can load directly to the program a processed NMR experiment file or add the NMR data by hand. The experimental data (1D or 2D experiments) is compared to the predicted one based on the structures proposed by the LC-HRMS analysis, keeping only those solutions where the predicted and experimental NMR data match. 

Enabling Efficient Late‐Stage Functionalization of Drug‐Like Molecules with LC‐MS and Reaction‐Driven Data Processing

European Journal of  Organic Chemistry, 2017 

Huifang Yao, Yong Liu, Sriram Tyagarajan, Eric Streckfuss, Mikhail Reibarkh,  Kuanchang Chen,  Ismael Zamora,  Fabien Fontaine,  Laura Goracci,  Roy Helmy,  Kevin P. Bateman,  Shane W. Krska

Abstract

Late‐stage functionalization (LSF) through C–H functionalization of drug leads is a powerful synthetic strategy for drug discovery. A key challenge in LSF is that multiple regioisomeric products are often generated, which requires slow and laborious product isolation and structure confirmation steps. To address this, an analytical approach using LC‐HR‐MS/MS coupled with automated chemically aware data processing was developed. Using this method to analyze reaction screening arrays based on three common C–H functionalization chemistries with a set of marketed drugs, the relative amount and localization of chemical modification could be determined for each regioisomeric product generated in the screening.

This approach allows one to construct a workflow in which the various regioisomeric products of a given transformation are triaged according to their site of modification, allowing downstream isolation and structure elucidation efforts to focus on those analogues of highest interest, leading to an overall increase in productivity of the LSF strategy. 

A case study of the MassChemSite Reaction Tracking Workflow: Detecting and identifying byproducts during PROTAC synthesis

68th ASMS Conference on Mass Spectrometry and Allied Topics Reboot. Online. June 2020

Abstract

PROTACs are heterobifunctional small molecules composed of a ligand for a protein of interest (POI) and an E3 ligase recruiter connected through a linker.1 Instead of inhibiting the protein functions, PROTACs promote the formation of a ternary complex with POI and E3 ligase, inducing POI poly-ubiquitylation and its successive proteasomal-dependent degradation. 

This appealing technology has already attracted great attention from both academia and industry, and the optimization of PROTACs’ synthetic procedures is now needed. As an example, to automatically find byproducts formed during the synthesis of PROTAC, in this poster we will present the use of the Reaction Tracking workflow included in MassChemsite. This workflow is designed for untargeted multicomponent reactions. 

Structural elucidation tools to enhance organic synthesis productivity

66th ASMS Conference on Mass Spectrometry and Allied Topics, San Diego (United States of America) … 06 June 2018 

Abstract

The majority of organic synthesis workflows end up with the synthesis of at least few milligrams of pure compound, which structure is corroborated by Nuclear Magnetic Resonance spectroscopy.  Therefore, it needs first to use relatively large quantities of initial materials and purify the reaction crude before knowing if the desired compound has been obtained. The chemist uses LCMS prior purification to identify if a peak with the expected mass was formed. Nowadays there are Mass Spectrometry techniques that with the aid of computational algorithms can determine if the desired compound was obtained, as well as if there were other interesting compounds formed with minimal amount of sample and without the need of purification, making the synthetic process more time/cost effective. 

Software-aided workflow for predicting protease-specific cleavage sites using physicochemical properties of the natural and unnatural amino acids in peptide-based drug discovery

January 2019.

Radchenko T; Fontaine F; Morettoni L; Zamora I

Abstract

Peptide drugs have been used in the treatment of multiple pathologies. During peptide discovery, it is crucially important to be able to map the potential sites of cleavages of the proteases. This knowledge is used to later chemically modify the peptide drug to adapt it for the therapeutic use, making peptide stable against individual proteases or in complex medias. In some other cases it needed to make it specifically unstable for some proteases, as peptides could be used as a system to target delivery drugs on specific tissues or cells. The information about proteases, their sites of cleavages and substrates are widely spread across publications and collected in databases such as MEROPS.

Therefore, it is possible to develop models to improve the understanding of the potential peptide drug proteolysis. We propose a new workflow to derive protease specificity rules and predict the potential scissile bonds in peptides for individual proteases. WebMetabase stores the information from experimental or external sources in a chemically aware database where each peptide and site of cleavage is represented as a sequence of structural blocks connected by amide bonds and characterized by its physicochemical properties described by Volsurf descriptors. Thus, this methodology could be applied in the case of non-standard amino acid. A frequency analysis can be performed in WebMetabase to discover the most frequent cleavage sites.

These results were used to train several models using logistic regression, support vector machine and ensemble tree classifiers to map cleavage sites for several human proteases from four different families (serine, cysteine, aspartic and matrix metalloproteases). Finally, we compared the predictive performance of the developed models with other available public tools PROSPERous and SitePrediction.