Unveiling the Solvent Effect: DMSO Interaction with Human Nerve Growth Factor and Its Implications for Drug Discovery
<b>Background:</b> The Nerve Growth Factor (NGF) is essential for neuronal survival and function and represents a key therapeutic target for pain and inflammation-related disorders, as well as for neurodegenerative diseases. Small-molecule antagonists of human NGF (hNGF) offer advantages...
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2025-07-01
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| author | Francesca Paoletti Tjaša Goričan Alberto Cassetta Jože Grdadolnik Mykola Toporash Doriano Lamba Simona Golič Grdadolnik Sonia Covaceuszach |
| author_facet | Francesca Paoletti Tjaša Goričan Alberto Cassetta Jože Grdadolnik Mykola Toporash Doriano Lamba Simona Golič Grdadolnik Sonia Covaceuszach |
| author_sort | Francesca Paoletti |
| collection | DOAJ |
| description | <b>Background:</b> The Nerve Growth Factor (NGF) is essential for neuronal survival and function and represents a key therapeutic target for pain and inflammation-related disorders, as well as for neurodegenerative diseases. Small-molecule antagonists of human NGF (hNGF) offer advantages over monoclonal antibodies, including oral availability and reduced immunogenicity. However, their development is often hindered by solubility challenges, necessitating the use of solvents like dimethyl sulfoxide (DMSO). This study investigates whether DMSO directly interacts with hNGF and affects its receptor-binding properties. <b>Methods:</b> Integrative/hybrid computational and experimental biophysical approaches were used to assess DMSO-NGF interaction by combining machine-learning tools and Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared (FT-IR) spectroscopy, Differential Scanning Fluorimetry (DSF) and Grating-Coupled Interferometry (GCI). These techniques evaluated binding affinity, conformational stability, and receptor-binding dynamics. <b>Results:</b> Our findings demonstrate that DMSO binds hNGF with low affinity in a specific yet non-disruptive manner. Importantly, DMSO does not induce significant conformational changes in hNGF nor affect its interactions with its receptors. <b>Conclusions:</b> These results highlight the importance of considering solvent–protein interactions in drug discovery, as these low-affinity yet specific interactions can affect experimental outcomes and potentially alter the small molecules binding to the target proteins. By characterizing DMSO-NGF interactions, this study provides valuable insights for the development of NGF-targeting small molecules, supporting their potential as effective alternatives to monoclonal antibodies for treating pain, inflammation, and neurodegenerative diseases. |
| format | Article |
| id | doaj-art-751d189207bd4852b91cd46e3d60072f |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-751d189207bd4852b91cd46e3d60072f2025-08-20T02:47:17ZengMDPI AGMolecules1420-30492025-07-013014303010.3390/molecules30143030Unveiling the Solvent Effect: DMSO Interaction with Human Nerve Growth Factor and Its Implications for Drug DiscoveryFrancesca Paoletti0Tjaša Goričan1Alberto Cassetta2Jože Grdadolnik3Mykola Toporash4Doriano Lamba5Simona Golič Grdadolnik6Sonia Covaceuszach7Institute of Crystallography-C.N.R.-Trieste Outstation, 34149 Trieste, ItalyLaboratory for Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, 1001 Ljubljana, SloveniaInstitute of Crystallography-C.N.R.-Trieste Outstation, 34149 Trieste, ItalyLaboratory for Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, 1001 Ljubljana, SloveniaInstitute of Crystallography-C.N.R.-Trieste Outstation, 34149 Trieste, ItalyInstitute of Crystallography-C.N.R.-Trieste Outstation, 34149 Trieste, ItalyLaboratory for Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, 1001 Ljubljana, SloveniaInstitute of Crystallography-C.N.R.-Trieste Outstation, 34149 Trieste, Italy<b>Background:</b> The Nerve Growth Factor (NGF) is essential for neuronal survival and function and represents a key therapeutic target for pain and inflammation-related disorders, as well as for neurodegenerative diseases. Small-molecule antagonists of human NGF (hNGF) offer advantages over monoclonal antibodies, including oral availability and reduced immunogenicity. However, their development is often hindered by solubility challenges, necessitating the use of solvents like dimethyl sulfoxide (DMSO). This study investigates whether DMSO directly interacts with hNGF and affects its receptor-binding properties. <b>Methods:</b> Integrative/hybrid computational and experimental biophysical approaches were used to assess DMSO-NGF interaction by combining machine-learning tools and Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared (FT-IR) spectroscopy, Differential Scanning Fluorimetry (DSF) and Grating-Coupled Interferometry (GCI). These techniques evaluated binding affinity, conformational stability, and receptor-binding dynamics. <b>Results:</b> Our findings demonstrate that DMSO binds hNGF with low affinity in a specific yet non-disruptive manner. Importantly, DMSO does not induce significant conformational changes in hNGF nor affect its interactions with its receptors. <b>Conclusions:</b> These results highlight the importance of considering solvent–protein interactions in drug discovery, as these low-affinity yet specific interactions can affect experimental outcomes and potentially alter the small molecules binding to the target proteins. By characterizing DMSO-NGF interactions, this study provides valuable insights for the development of NGF-targeting small molecules, supporting their potential as effective alternatives to monoclonal antibodies for treating pain, inflammation, and neurodegenerative diseases.https://www.mdpi.com/1420-3049/30/14/3030Nerve Growth Factor (NGF)dimethyl sulfoxide (DMSO)drug discoveryNuclear Magnetic Resonance (NMR)Fourier Transform Infrared (FT-IR) spectroscopyDifferential Scanning Fluorimetry (DSF) |
| spellingShingle | Francesca Paoletti Tjaša Goričan Alberto Cassetta Jože Grdadolnik Mykola Toporash Doriano Lamba Simona Golič Grdadolnik Sonia Covaceuszach Unveiling the Solvent Effect: DMSO Interaction with Human Nerve Growth Factor and Its Implications for Drug Discovery Molecules Nerve Growth Factor (NGF) dimethyl sulfoxide (DMSO) drug discovery Nuclear Magnetic Resonance (NMR) Fourier Transform Infrared (FT-IR) spectroscopy Differential Scanning Fluorimetry (DSF) |
| title | Unveiling the Solvent Effect: DMSO Interaction with Human Nerve Growth Factor and Its Implications for Drug Discovery |
| title_full | Unveiling the Solvent Effect: DMSO Interaction with Human Nerve Growth Factor and Its Implications for Drug Discovery |
| title_fullStr | Unveiling the Solvent Effect: DMSO Interaction with Human Nerve Growth Factor and Its Implications for Drug Discovery |
| title_full_unstemmed | Unveiling the Solvent Effect: DMSO Interaction with Human Nerve Growth Factor and Its Implications for Drug Discovery |
| title_short | Unveiling the Solvent Effect: DMSO Interaction with Human Nerve Growth Factor and Its Implications for Drug Discovery |
| title_sort | unveiling the solvent effect dmso interaction with human nerve growth factor and its implications for drug discovery |
| topic | Nerve Growth Factor (NGF) dimethyl sulfoxide (DMSO) drug discovery Nuclear Magnetic Resonance (NMR) Fourier Transform Infrared (FT-IR) spectroscopy Differential Scanning Fluorimetry (DSF) |
| url | https://www.mdpi.com/1420-3049/30/14/3030 |
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