Issue 2, 2019

A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors

Abstract

Cyclophilins (Cyps) are a major family of drug targets that are challenging to prosecute with small molecules because the shallow nature and high degree of conservation of the active site across human isoforms offers limited opportunities for potent and selective inhibition. Herein a computational approach based on molecular dynamics simulations and free energy calculations was combined with biophysical assays and X-ray crystallography to explore a flip in the binding mode of a reported urea-based Cyp inhibitor. This approach enabled access to a distal pocket that is poorly conserved among key Cyp isoforms, and led to the discovery of a new family of sub-micromolar cell-active inhibitors that offer unprecedented opportunities for the development of next-generation drug therapies based on Cyp inhibition. The computational approach is applicable to a broad range of organic functional groups and could prove widely enabling in molecular design.

Graphical abstract: A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors

Supplementary files

Article information

Article type
Edge Article
Submitted
27 ago 2018
Accepted
14 out 2018
First published
23 out 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2019,10, 542-547

A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors

A. De Simone, C. Georgiou, H. Ioannidis, A. A. Gupta, J. Juárez-Jiménez, D. Doughty-Shenton, E. A. Blackburn, M. A. Wear, J. P. Richards, P. N. Barlow, N. Carragher, M. D. Walkinshaw, A. N. Hulme and J. Michel, Chem. Sci., 2019, 10, 542 DOI: 10.1039/C8SC03831G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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