Shape Similarity by Fractal Dimensionality: An Application in the de novo Design of (−)‐Englerin A Mimetics

Abstract

Molecular shape and pharmacological function are interconnected. To capture shape, the fractal dimensionality concept was employed, providing a natural similarity measure for the virtual screening of de novo generated small molecules mimicking the structurally complex natural product (−)‐englerin A. Two of the top‐ranking designs were synthesized and tested for their ability to modulate transient receptor potential (TRP) cation channels which are cellular targets of (−)‐englerin A. Intracellular calcium assays and electrophysiological whole‐cell measurements of TRPC4 and TRPM8 channels revealed potent inhibitory effects of one of the computer‐generated compounds. Four derivatives of this identified hit compound had comparable effects on TRPC4 and TRPM8. The results of this study corroborate the use of fractal dimensionality as an innovative shape‐based molecular representation for molecular scaffold‐hopping.

Novel botanical active component derivatives containing carboxamide and 1,3,4-Thiadiazole thioether moieties: Design, synthesis, and inhibitory activity

“…As shown in Scheme 1 , using the botanical active components of carvacrol, thymol, guaiacol, and sesamol as the lead structures, intermediates 2 and 4 were prepared using the methods that have been previously reported ( Friedrich et al, 2020 ; Yu et al, 2022 ).…”

Cheminformatics in Natural Product‐based Drug Discovery

“…In a follow‐up study, the above‐mentioned ranking approach was extended to take into account also the 3D molecular shape similarity (based on global fractal dimensionality) of the 323 designs [165] . One of two compounds selected by this approach ( 11 ) was again confirmed as potent inhibitor of TRPC4 and TRPM8 channels.…”