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

被引：5

作者：

Friedrich, Lukas ^{[1
]}

Byrne, Ryan ^{[1
]}

Treder, Aaron ^{[2
]}

Singh, Inderjeet ^{[2
]}

Bauer, Christoph ^{[1
]}

Gudermann, Thomas ^{[2
,3
,4
]}

Schnitzler, Michael ^{[2
,3
]}

Storch, Ursula ^{[2
,5
]}

Schneider, Gisbert ^{[1
]}

机构：

[1] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Vladimir Prelog Weg 4, CH-8093 Zurich, Switzerland

[2] Ludwig Maximilians Univ Munchen, Walther Straub Inst Pharmacol & Toxicol, Goethestr 33, D-80336 Munich, Germany

[3] Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Biedersteiner Str 29, D-80802 Munich, Germany

[4] German Ctr Lung Res, Comprehens Pneumol Ctr Munich CPC M, Max Lebsche Pl 31, D-81377 Munich, Germany

[5] Ludwig Maximilians Univ Munchen, Inst Cardiovasc Prevent IPEK, Pettenkoferstr 8a & 9, D-80336 Munich, Germany

来源：

CHEMMEDCHEM | 2020年 / 15卷 / 07期

基金：

欧盟地平线“2020”;

关键词：

natural products; virtual screening; drug discovery; molecular shape; computer-assisted drug design; MACROMOLECULAR TARGETS; SEARCH; POTENT;

D O I：

10.1002/cmdc.202000017

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：566 / 570

页数：5