Submission Details

Design Rationale:

These designs aim to present a heteroaromatic nitrogen to the side chain amide NH of N142 and can be regarded as analogous to sulfone PET-UNK-4880b143-1 and amides PET-UNK-49566573-1 and PET-UNK-49566573-2. I think that the basic idea could be tested with Design 1 (1,2,3-triazole) and although I’ve included three additional designs (pyridazine, 1,3,4-oxadiazole, 1,3,4-thiadazole) in case interesting activity is observed for design 1 (or if the designs are of interest to the design team). I would anticipate that potency gains relative to PET-UNK-29afea89-2 will be greater for PET-UNK-4880b143-1, PET-UNK-49566573-1, PET-UNK-49566573-2 than for any of the designs in the current submission. My recommendation would be to start by synthesizing Design 1, only proceeding with Designs 2, 3 or 4 if interesting activity is observed.

Other Notes:

Protein-ligand complexes were energy minimized with Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at their crystallographic positions) using the A chain of the P0157 crystal structure (ligand: PET-UNK-29afea89-2) in which the side chain amide of N142 has been rotated by 180 degree prior to energy minimization. The PDB file associated with the submission contains the following structures [1] Protein from energy minimized structure of complex with conformation 1 of Design 1 (1,2,3-triazole) [2] Crystallographic ligand: PET-UNK-29afea89-2) from P0157 A chain [3-5] Predicted binding modes for PET-UNK-4880b143-1, PET-UNK-49566573-1 and PET-UNK-49566573-2 [6-9] Predicted binding modes for designs 1-4.

Inspired By:

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