Submission Details

Design Rationale:

Structure-based design combining: 1) X_0678 and X_0107 (targeting the S1 and S1' pockets) 2) X_0161, X_0195, X_0946 (providing a vector to target the S3 pocket from the S1' pocket) 3) The recently reported niclosamide hit (not reviewed pre-print, https://www.biorxiv.org/content/10.1101/2020.02.25.965582v2) The N-phenylbenzamide scaffold of Niclosamide may bind in similar way as the benzamide (X_0678) and (di)phenylurea (X_0434) scaffolds observed in several fragments. Obviously early days and appreciating that recognising simple substructures between hits and assuming they bind in a similar manner can be deceiving. I have therefore also included 9 designs to efficiently explore simple SAR around the putative niclosamide hit, which can be helpful to provide more confidence in the binding mode hypothesis and customise/extend the scope of the associated designs. The cross-over designs include: - Incorporation of the 3-pyridine nitrogen H-bond acceptor targeting H163 in the S1 pocket into the niclosamide N-phenylbenzamide scaffold - Exploration of different vectors and linkers to grow from the lipophilic S1' pocket into the S3 pocket with and without the sulphonamide of X_0161/X_0195/X_0946

Other Notes:

Structure-based design combining: 1) X_0678 and X_0107 (targeting the S1 and S1' pockets) 2) X_0161, X_0195, X_0946 (providing a vector to target the S3 pocket from the S1' pocket) 3) The recently reported niclosamide hit (not reviewed pre-print, https://www.biorxiv.org/content/10.1101/2020.02.25.965582v2) The N-phenylbenzamide scaffold of Niclosamide may bind in similar way as the benzamide (X_0678) and (di)phenylurea (X_0434) scaffolds observed in several fragments. Obviously early days and appreciating that recognising simple substructures between hits and assuming they bind in a similar manner can be deceiving. I have therefore also included 9 designs to efficiently explore simple SAR around the putative niclosamide hit, which can be helpful to provide more confidence in the binding mode hypothesis and customise/extend the scope of the associated designs. The cross-over designs include: - Incorporation of the 3-pyridine nitrogen H-bond acceptor targeting H163 in the S1 pocket into the niclosamide N-phenylbenzamide scaffold - Exploration of different vectors and linkers to grow from the lipophilic S1' pocket into the S3 pocket with and without the sulphonamide of X_0161/X_0195/X_0946

Inspired By:

MAT-POS-7dfc56d9-1

ALE-HEI-f28a35b5-9

MAK-UNK-6435e6c2-8

AAR-POS-d2a4d1df-15

AAR-POS-d2a4d1df-4