November 13, 2020
by Yalda Liaghati, Marketing Communications Specialist, ACD/Labs
ACD/Labs’ Virtual NMR Software Symposium took place a few weeks ago. This event was organized to virtually gather the NMR community in the absence of face-to-face events during the pandemic. The event featured diverse and engaging presentations by NMR experts from Merck & Co., JEOL, and AstraZeneca, where each speaker shared a recent exciting development in their R&D workflow.
Not only was it fascinating to gather with150 NMR users from over 25 countries for a few hours, but also as an NMR spectroscopist, I really enjoyed the presentations. In this blog, I will share the key concepts and top takeaways from each presentation for our interested readers.
Takeaway #1: The CASE-DFT method is a combination of AI and DFT approaches.
The Symposium kicked off with a presentation by Alexei Buevich, principal scientist at Merck & Co., on “Enhancing Computer-Assisted Structure Elucidation (CASE) with DFT Analysis of J-Couplings”. Alexei has been using ACD/Structure Elucidator Suite for few years has been collaborating in the development of the software throughout this time He started by highlighting how quantum mechanical calculations have improved and enhanced CASE and other artificial intelligence expert systems. Subsequently, a brief background on the application of CASE systems to elucidate a structure without human intervention was provided.
In addition, we learned that Density functional theory (DFT) analysis of the chemical shift is synergistic to CASE analysis since it broadens the range of structural problems that can be tackled to include molecules with unusual scaffolds, configurational isomers, and flexible molecules. It is quite powerful to add configuration analysis to isomers using a chemical shift criterion and enable the flexible molecule potentially be a part of CASE DFT studies. The addition of the DFT analysis of J-couplings to CASE expert systems not only increases the robustness of the CASE method by complimenting structure elucidation based on chemical shifts with orthogonal structural parameters, but also serves as a verification method for experimental data integrity. This will further improve CASE analysis by reducing errors in the data gathered.
Takeaway #2: Full automation from sample acquisition to verification is feasible for challenging samples.
The process of automating the structure verification of natural products and fluorine containing products was explored by Manuel Perez, Head of NMR Business Development Europe at JEOL, during the next presentation.
A vast number of samples are studied on a daily basis within a modern high-throughput lab workflow, which can make manual structure verification a daunting task in such environments. Automated Structure Verification (ASV) is an excellent tool to help analysts speed up this process and significantly reduce the number of samples that require manual attention. Manuel initially highlighted how special focus should be placed on the hardware settings, as well as acquiring experiments based on specific workflows to achieve a successful automation deployment. Following the proof-of-concept trials of the automation software using established structures, a diverse structural dataset with complicated compounds was studied. The results showed that in over 90% of the cases, automation was able to verify the structures, many of which were heavily fluorinated or steroid type medicinal compounds.
Additionally, it was revealed that simplification of 1D and 2D spectra by decoupling techniques, and the resulting S/N gain can lead to successful automated verification, which would have otherwise required further inspection. Further, effective visualization of analysis results using the color-coded plate scheme greatly helps to quickly identify and analyze only the flagged samples by the expert and ultimately saves time and effort.
Takeaway #3: Structural conformation studies can be employed to optimize drug design efforts.
A key question addressed by 1D NMR conformational analysis in designing potent drugs is whether the bioactive conformation is highly populated by the free ligand in the solution. Our final guest speaker, Amber Balazs, Associate Principal Scientist at AstraZeneca, discussed this in her presentation entitled “Free Ligand 1D NMR Conformational Signatures to Aid Medicinal Chemistry Design of Potent Drug Candidates.”
1D 1H NMR inherently provides information on 3D structural conformations and the preferred conformation in solutions. This adopted conformation of a free ligand greatly impacts bioactivity and physiochemical properties. Therefore, combining 1D NMR conformational signatures with measured potency data is a powerful technique to effectively guide medicinal chemistry decisions within design cycles for compound optimization.
Consequently, using the conformational signatures provided by NMR, medicinal chemists can enhance drug design efforts by increasing rigidity and locking the bioactive conformation to improve drug potency. Furthermore, synthetic efforts can be reduced by using diagnostic chemical shifts of bioactive confirmations to understand if lack of potency arises from wrong free ligand confirmation or poor ligand binding.
If you are interested in a more in-depth look into the talks from this virtual NMR event watch the full presentations from Merck & Co., JEOL, and AstraZeneca on demand here.