Discovering Drug Seeds by Practical NMR Strategies

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Discovering Drug Seeds by Practical NMR Strategies

Steven LaPlante

University of Quebec INRS-IAF, Canada

Small molecule drugs continue to be crucial for combating diseases. This presentation will convey the critical role NMR has been playing for discovering the seeds for new drugs starting from substrate peptides, high-throughput screens and fragment-based screens. Central to all the examples was the need to better understand the properties of small molecules when free in solution and to decipher the various types of binding to macromolecules. To do so, appropriate NMR methods/strategies were developed to prioritize quality ligands for downfield medicinal chemistry purposes. Examples will be shown where NMR strategies revealed compound solution behavior (solubility, aggregation, atropisomer chirality), exposed target protein features (folding and changes), and determined stoichiometric binding attributes (see Figures 1 and 2).

Figure 1. NMR ligand-detection methods. Figure 2. NMR methods for selecting stoichiometric

ligand binding.

Acknowledgments: Harvard Medical School: G. Wagner, G. Heffron, P. Coote, H. Arthanari; NMX

Research and Solutions Inc.: F. Bilodeau; Boehringer Ingelheim.

STD (2 spectra)

DLB (2 spectra)

Ligand Detection Methods For Fragment Screening CPMG (10 spectra) WaterLOGSY STD (difference) 1_{H free ligands} (10 spectra)

1_{H Methyl Region of Target Protein}

1_H-15_{N TROSY}

19_{F Binding and Competition} (1) free 2 (2) 2 : helicase (1:0.4) (3) 2 : helicase (1:0.8) (4) 2 : helicase : d(U)24 (1:0.8:0.4) (5) 2 : helicase : d(U)24 (1:0.8:0.8) (1) free 1 (2) 1 : helicase (1 : 0.06) (3) 1 : helicase : 2 (1 : 0.06 : 1)

1_{H DLB Binding and Competition}