Fragment-Based Drug Discovery (FBDD) and validation of small molecules binders using NMR has emerged as a powerful method in early-stage drug development. This post explores the general use of analytical techniques and innovative screening software solutions that optimize the process, enabling researchers to identify promising drug candidates with precision.<h4>Analytical Techniques in Fragment-Based Drug Discovery</h4>To kickstart the FBDD journey, researchers employ ligand- or protein-observed NMR methods to detect binders from a library of small compounds. These analytical techniques, such as Nuclear Magnetic Resonance (NMR) spectroscopy, provide valuable data that play a crucial role in structurally characterizing potential drug molecules.<h4>Efficient Screening Tools for Hit Finding</h4>In the field of FBDD, researchers can benefit from a suite of powerful screening tools, including Mnova Screen 1D and <a target="_blank" rel="noopener noreferrer" href="https://icpms.labrulez.com/products/1597">Mnova Screen 2D</a>, designed to efficiently analyze both 1D and 2D NMR data. These tools facilitate the analysis of 1D 1H or 19F screening data, including STD, T1ρ, WaterLogsy, and CPMG methods. Additionally, they allow batch processing of protein-observed 2D NMR spectra, such as 1H-15N or 1H-13C SOFAST HMQC. Automated peak picking and Q-Score ranking significantly expedite the identification and ranking of potential binding hits, empowering researchers to make data-driven decisions.<h4>Measuring Binding Affinities with Precision</h4>For researchers exploring multiple titration series, another piece of software, <a target="_blank" rel="noopener noreferrer" href="https://icpms.labrulez.com/products/1592">Mnova Binding</a>, offers seamless batch processing of 2D NMR titration data. By fitting chemical shift perturbations (CSP) along titration curves, this tool accurately measures binding affinities (KD). Additionally, it automatically selects and averages individual KD values, facilitating comprehensive analysis.<h4>Unified Software Solutions for FBDD</h4>As illustrated in Fig 1, by presenting these software solutions, including Mnova Screen 1D, Mnova Screen 2D, and Mnova Binding, in a cohesive manner, researchers can benefit from a comprehensive toolbox with the same user-friendly interface to maximize the impact of NMR data, paving the way for innovative drug discoveries.<img src="https://storage.googleapis.com/labrulez-bucket-strapi-h3hsga3/Mestrelab_Research_Figure_1_Illustration_of_fragment_based_drug_discovery_using_1_D_or_2_D_NMR_and_the_Mnova_software_tools_for_analyzing_such_data_c6b313ee88.jpg" alt="Mestrelab Research:Figure 1. Illustration of fragment-based drug discovery using 1D or 2D NMR, and the Mnova software tools for analyzing such data: Screen for 1D ligand-observed data such as STD, T1r, WaterLogsy and CPMG; Screen 2D for 2D protein-observed data such 1H-15N or 1H-13C SOFAST HMQC; Binding for titration series using 2D 1H-15N, 1H-13C, or 1H-13C/15N dual SOFAST-HMQC etc." srcset="https://storage.googleapis.com/labrulez-bucket-strapi-h3hsga3/thumbnail_Mestrelab_Research_Figure_1_Illustration_of_fragment_based_drug_discovery_using_1_D_or_2_D_NMR_and_the_Mnova_software_tools_for_analyzing_such_data_c6b313ee88.jpg 245w," sizes="100vw" width="1600" height="686"><h4>Conclusion</h4>In conclusion, this post highlights the significance of Innovative screening software solutions in advancing Fragment-Based Drug Discovery by NMR. By exploring the power of these screening tools, researchers gain a deeper understanding of potential drug molecules, accelerating the drug development process. Let’s embrace the potential of software solutions to revolutionize FBDD by NMR, uncovering new therapeutic possibilities for the future.<a target="_blank" rel="noopener noreferrer" href="https://mestrelab.com/contact">Contact us</a> if you would like to talk to one of our experts about these NMR screening tools.You can also watch a demonstration of a related application in one of our webinars held in October 2023. “<a target="_blank" rel="noopener noreferrer" href="https://mestrelab.com/webinars/fragment-based-drug-discovery-application-webinar.html">Efficiently Driving Protein-based NMR Fragment Screening and Lead Discovery</a>”

Optimizing Fragment-Based Drug Discovery by NMR: A Deep Dive into Mnova Screening Software Solutions

<h4>The Role of Computers in Structural Problem Resolution:</h4>The use of computers is not just helpful but often essential in resolving structural problems. Computer-based structural elucidation (CASE) such as <a target="_blank" rel="noopener noreferrer" href="https://icpms.labrulez.com/products/1599">Mnova Structure Elucidation</a> proves invaluable, particularly in navigating challenges posed by molecules with a poor hydrogen to carbon ratio. Computational techniques become increasingly relevant when determining stereochemical configuration and conformation.<h4>Steps in Computational Structural Elucidation:</h4><ul><li>Generation of Stereoisomers: Automation alleviates the tedium associated with generating diastereoisomers.</li><li>Conformational Search: Molecular mechanics force-fields aid in exploring conformational space.</li><li>Structural Refinement: Density functional theory (DFT) geometry optimization refines structural accuracy.</li><li>NMR Properties Computation/Analysis: Various NMR observables contribute to structural analysis.</li></ul><img src="https://storage.googleapis.com/labrulez-bucket-strapi-h3hsga3/Mestrelab_Research_A_Symphony_of_NMR_Data_Enhancing_Structural_Elucidation_080945b762.jpg" alt="Mestrelab Research: A Symphony of NMR Data: Enhancing Structural Elucidation" srcset="https://storage.googleapis.com/labrulez-bucket-strapi-h3hsga3/thumbnail_Mestrelab_Research_A_Symphony_of_NMR_Data_Enhancing_Structural_Elucidation_080945b762.jpg 245w," sizes="100vw" width="936" height="559"><h4>Employing Different NMR Observables:</h4>Utilizing Different NMR Observables: The application of various NMR observables adds a subtle dimension to structural analysis, allowing for a comprehensive understanding of molecular characteristics. Each observable contributes unique insights, enhancing the precision and reliability of the elucidation process.<h5>Beyond the Use of NOE Effects:</h5>While NOE effects traditionally serve a qualitative role in structural analysis, their potential goes beyond. Rigorous analysis of kinetic NOESY/ROESY 1D or 2D experiments, following well-described protocols, yields accurate internuclear proton-proton distances. This data proves exceptionally effective in conformational analysis, particularly in complex medicinal chemistry problems. (1)<h5>J-Couplings and Karplus-like Relationships:</h5>Vicinal J-couplings provide essential dihedral angle information, crucial for stereochemical analysis. Empirical Karplus-like relationships allow quantitative use aspect of this information. Additionally, DFT predictions offer not only more accurate data but also the flexibility to incorporate various couplings, such as geminal 1J(C-H), 2J(C-H) couplings, or even the possibility to establish Karplus relationships based on DFT analysis of model systems. <a target="_blank" rel="noopener noreferrer" href="https://mestrelab.com/resources/stereofitter-how-to-use-j-couplings.html">How to use J-couplings</a>.<h5>Chemical Shift Analysis Supported by DFT Predictions:</h5>Chemical shift analysis of 13C and 1H data, supported by DFT computations, has become increasingly popular for structural elucidation of natural products. This method proves valuable not only for de novo structural determination but also for the revision of already reported compounds.<h5>Residual Dipolar Couplings (RDC):</h5>RDCs emerge as a formidable tool for establishing configuration and conformation due to their capability to correlate the configuration of far away stereocenters. (2) &nbsp;They are applicable to a spectrum of structural problems, ranging from classical natural product elucidation, to &nbsp;medicinal chemistry applications such as the conformation guided design of cyclic peptides. (3) Weakly-aligning media, such as different types of liquid crystals or polymer gels, provides a user-friendly approach to the measurement of RDCs. (4)In summary, the strategic incorporation of these diverse NMR observables enhances the analytical arsenal, enabling a thorough and efficient exploration of structural complexities. Mestrelab’s commitment to providing tools like <a target="_blank" rel="noopener noreferrer" href="https://icpms.labrulez.com/products/1598">Mnova StereoFitter</a> empowers users to seamlessly integrate and analyze this wealth of NMR and structural data for conclusive structural elucidation.You can watch a demonstration of a related application in one of our webinars held in November 2023. &nbsp;“<a target="_blank" rel="noopener noreferrer" href="https://mestrelab.com/webinars/webinar-pharmaceutical-molecule-characterization-and-structure-analysis.html">Advanced NMR Strategies for Pharmaceutical Molecule Characterization and Structure Analysis</a>”

A Symphony of NMR Data: Enhancing Structural Elucidation

Play FID is a new tool included within the latest version of <a target="_blank" rel="noopener noreferrer" href="https://icpms.labrulez.com/products/1081">Mnova</a> 15.0.1. The purpose of Play FID is to provide an auditory representation of NMR data, enhancing the interpretation and understanding of NMR spectra. This feature is especially useful in educational settings and for aiding the identification of specific functional groups in a spectrum. It introduces a unique approach by adding an auditory dimension to the typically visual analysis of NMR data.Discover the innovative intersection of sound and science in our recently published article on auditory NMR spectroscopy, “<a target="_blank" rel="noopener noreferrer" href="https://mestrelab.com/articles/molecular-melodies-unraveling-the-hidden-harmonies-of-nmr-spectroscopy.html">Molecular Melodies: Unraveling the Hidden Harmonies of NMR Spectroscopy</a>“<blockquote>Iria Pérez: "As an engineer, I always aspired to make significant contributions to science. Little did I know that my work would one day enable us to hear molecules. I believe in the immersive potential of Play FID for scientifical research, education and art, since even I enriched my knowledge about NMR through my involvement with Play FID. I’m grateful to have worked with a highly talented team, who even created some unique compositions I had the pleasure enjoy. I look forward to seeing how this feature will be explored in many fields…”Gavin Shear: “When I worked for another NMR software provider, by far the most requested feature I got from students, was the one from MestReC that played the FID as a sound. To see it come back to Mnova is glorious, I’m over the moon to be able to hear what my acquisitions sound like again – and even better than before – I can save the sounds and use them in compositions!…”Carlos Cobas: “More than 20 years ago, I introduced the capability to play NMR FIDs in MestReC. Ever since, I’ve been eager to extend this feature to Mnova, along with implementing long-considered enhancements. Now, I’m delighted to finally have the opportunity to bring this to fruition with the support of an exceptional team…”</blockquote>

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