Quadruple Target Evaluation of Diversity-Optimized Halogen-Enriched Fragments (HEFLibs) Reveals Substantial Ligand Efficiency for AP2-Associated Protein Kinase 1 (AAK1)
Fragment-based drug discovery is one of the most utilized approaches for the identification of novel weakly binding ligands, by efficiently covering a wide chemical space with rather few compounds and by allowing more diverse binding modes to be found. This approach has led to various clinical candi...
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| Format: | Article |
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2021.815567/full |
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| author | Marcel Dammann Markus Kramer Markus O. Zimmermann Frank M. Boeckler Frank M. Boeckler |
| author_facet | Marcel Dammann Markus Kramer Markus O. Zimmermann Frank M. Boeckler Frank M. Boeckler |
| author_sort | Marcel Dammann |
| collection | DOAJ |
| description | Fragment-based drug discovery is one of the most utilized approaches for the identification of novel weakly binding ligands, by efficiently covering a wide chemical space with rather few compounds and by allowing more diverse binding modes to be found. This approach has led to various clinical candidates and approved drugs. Halogen bonding, on the other hand, has gained traction in molecular design and lead optimization, but could offer additional benefits in early drug discovery. Screening halogen-enriched fragments (HEFLibs) could alleviate problems associated with the late introduction of such a highly geometry dependent interaction. Usually, the binding mode is then already dominated by other strong interactions. Due to the fewer competing interactions in fragments, the halogen bond should more often act as an anchor point for the binding mode. Previously, we proposed a fragment library with a focus on diverse binding modes that involve halogens for gaining initial affinity and selectivity. Herein, we demonstrate the applicability of these HEFLibs with a small set of diverse enzymes: the histone-lysine N-methyltransferase DOT1L, the indoleamine 2,3-dioxygenase 1 (IDO1), the AP2-associated protein kinase 1 (AAK1), and the calcium/calmodulin-dependent protein kinase type 1G (CAMK1G). We were able to identify various binding fragments via STD-NMR. Using ITC to verify these initial hits, we determined affinities for many of these fragments. The best binding fragments exhibit affinities in the one-digit micromolar range and ligand efficiencies up to 0.83 for AAK1. A small set of analogs was used to study structure-affinity relationships and hereby analyze the specific importance of each polar interaction. This data clearly suggests that the halogen bond is the most important interaction of fragment 9595 with AAK1. |
| first_indexed | 2024-04-11T19:51:46Z |
| format | Article |
| id | doaj.art-c476b76c0c654f17934ff5b5e83bb90a |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-11T19:51:46Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-c476b76c0c654f17934ff5b5e83bb90a2022-12-22T04:06:17ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462022-02-01910.3389/fchem.2021.815567815567Quadruple Target Evaluation of Diversity-Optimized Halogen-Enriched Fragments (HEFLibs) Reveals Substantial Ligand Efficiency for AP2-Associated Protein Kinase 1 (AAK1)Marcel Dammann0Markus Kramer1Markus O. Zimmermann2Frank M. Boeckler3Frank M. Boeckler4Lab for Molecular Design and Pharmaceutical Biophysics, Department of Pharmacy and Biochemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Tübingen, GermanyInstitute of Organic Chemistry, Eberhard Karls Universität Tübingen, Tübingen, GermanyLab for Molecular Design and Pharmaceutical Biophysics, Department of Pharmacy and Biochemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Tübingen, GermanyLab for Molecular Design and Pharmaceutical Biophysics, Department of Pharmacy and Biochemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Tübingen, GermanyInterfaculty Institute for Biomedical Informatics (IBMI), Eberhard Karls Universität Tübingen, Tübingen, GermanyFragment-based drug discovery is one of the most utilized approaches for the identification of novel weakly binding ligands, by efficiently covering a wide chemical space with rather few compounds and by allowing more diverse binding modes to be found. This approach has led to various clinical candidates and approved drugs. Halogen bonding, on the other hand, has gained traction in molecular design and lead optimization, but could offer additional benefits in early drug discovery. Screening halogen-enriched fragments (HEFLibs) could alleviate problems associated with the late introduction of such a highly geometry dependent interaction. Usually, the binding mode is then already dominated by other strong interactions. Due to the fewer competing interactions in fragments, the halogen bond should more often act as an anchor point for the binding mode. Previously, we proposed a fragment library with a focus on diverse binding modes that involve halogens for gaining initial affinity and selectivity. Herein, we demonstrate the applicability of these HEFLibs with a small set of diverse enzymes: the histone-lysine N-methyltransferase DOT1L, the indoleamine 2,3-dioxygenase 1 (IDO1), the AP2-associated protein kinase 1 (AAK1), and the calcium/calmodulin-dependent protein kinase type 1G (CAMK1G). We were able to identify various binding fragments via STD-NMR. Using ITC to verify these initial hits, we determined affinities for many of these fragments. The best binding fragments exhibit affinities in the one-digit micromolar range and ligand efficiencies up to 0.83 for AAK1. A small set of analogs was used to study structure-affinity relationships and hereby analyze the specific importance of each polar interaction. This data clearly suggests that the halogen bond is the most important interaction of fragment 9595 with AAK1.https://www.frontiersin.org/articles/10.3389/fchem.2021.815567/fullhalogen bondingfragment-based drug discoverysaturation transfer differenceisothermal titration calorimetryDOT1LCAMK1G |
| spellingShingle | Marcel Dammann Markus Kramer Markus O. Zimmermann Frank M. Boeckler Frank M. Boeckler Quadruple Target Evaluation of Diversity-Optimized Halogen-Enriched Fragments (HEFLibs) Reveals Substantial Ligand Efficiency for AP2-Associated Protein Kinase 1 (AAK1) Frontiers in Chemistry halogen bonding fragment-based drug discovery saturation transfer difference isothermal titration calorimetry DOT1L CAMK1G |
| title | Quadruple Target Evaluation of Diversity-Optimized Halogen-Enriched Fragments (HEFLibs) Reveals Substantial Ligand Efficiency for AP2-Associated Protein Kinase 1 (AAK1) |
| title_full | Quadruple Target Evaluation of Diversity-Optimized Halogen-Enriched Fragments (HEFLibs) Reveals Substantial Ligand Efficiency for AP2-Associated Protein Kinase 1 (AAK1) |
| title_fullStr | Quadruple Target Evaluation of Diversity-Optimized Halogen-Enriched Fragments (HEFLibs) Reveals Substantial Ligand Efficiency for AP2-Associated Protein Kinase 1 (AAK1) |
| title_full_unstemmed | Quadruple Target Evaluation of Diversity-Optimized Halogen-Enriched Fragments (HEFLibs) Reveals Substantial Ligand Efficiency for AP2-Associated Protein Kinase 1 (AAK1) |
| title_short | Quadruple Target Evaluation of Diversity-Optimized Halogen-Enriched Fragments (HEFLibs) Reveals Substantial Ligand Efficiency for AP2-Associated Protein Kinase 1 (AAK1) |
| title_sort | quadruple target evaluation of diversity optimized halogen enriched fragments heflibs reveals substantial ligand efficiency for ap2 associated protein kinase 1 aak1 |
| topic | halogen bonding fragment-based drug discovery saturation transfer difference isothermal titration calorimetry DOT1L CAMK1G |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2021.815567/full |
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