Tag: fragment screening

Cell cytoskeleton as target for new active agents

Cell cytoskeleton as target for new active agents

Through a unique combination of computer simulations and laboratory experiments, researchers at the Paul Scherrer Institute PSI have discovered new binding sites for active agents – against cancer, for example – on a vital protein of the cell cytoskeleton. Eleven of the sites hadn’t been known before. The study is published in the journal Angewandte Chemie International Edition.

The protein tubulin is an essential building block of the so-called cell cytoskeleton. In cells, tubulin molecules arrange themselves into tube-like structures, the microtubule filaments. These give cells their shape, aid in transporting proteins and larger cellular components, and play a crucial role in cell division.

Thus tubulin performs diverse functions in the cell and in doing so interacts with numerous other substances. “Tubulin can bind an astonishing number of different proteins and small molecules, several hundred for sure,” says Tobias Mühlethaler, a doctoral candidate in the PSI Laboratory of Biomolecular Research and first author of the study. The functions of the protein are guided by means of such bonds. Also, many drugs dock on tubulin and take effect, for example, by preventing cell division in tumours.

Read more on the PSI website

Image: The research team in front of the Swiss Light Source (from left): Andrea Prota, Tobias Mühlethaler and Michel Steinmetz


Credit: Paul Scherrer Institute/Mahir Dzambegovic

Massive fragment screen points way to new SARS-CoV-2 inhibitors

Massive fragment screen points way to new SARS-CoV-2 inhibitors

Experiment with 2533 fragments compounds generates chemical map to future antiviral agents 

New research published in Science Advances provides a template for how to develop directly-acting antivirals with novel modes of action, that would combat COVID-19 by suppressing the SARS-CoV-2 viral infection. The study focused on the macrodomain part of the Nsp3 gene product that SARS-CoV-2 uses to suppress the host cell’s natural antiviral response. This part of the virus’s machinery, also known as Mac1, is essential for its reproduction: previous studies have shown that viruses that lack it cannot replicate in human cells, suggesting that blocking it with a drug would have the same effect.  

The study involved a crystallographic fragment screen of the Nsp3 Mac1 protein by an open science collaboration between researchers from the University of Oxford, the XChem platform at Diamond, and researchers from the QCRG Structural Biology Consortium at the University of California San Francisco.  The international effort discovered 234 fragment compounds that directly bind to sites of interest on the surface of the protein, and map out chemical motifs and protein-compound interactions that researchers and pharmaceutical companies can draw on to design compounds that could be developed into antiviral drugs.  This work is thus foundational for preparing for future pandemics.   

Read more on the Diamond website

Image: Principal Beamline Scientist on I04-1, Frank von Delft

Credit: Diamond Light Source