Numbercrunching to find a stable target for inhibiting the SARS-CoV-2 virus

The heart-shaped SARS-CoV-2 main protease
 consists of two protomers (blue and grey),
and is involved in processing viral polyproteins
A prototypical small molecule inhibitor (yellow)
is docked to the active site of the protease.

In the absence of a vaccine or an approved effective therapy against COVD-19, there is an interest in repositioning existing drugs or developing new inhibitors against viral targets.

A collaborative project between Monash and RMIT Universities is aimed at identifying and validating small molecules that can interact with or inhibit the active site of the SARS-CoV-2 main protease.

The protease is involved in processing viral polyproteins, and by blocking this protease viral replication can be inhibited.  With the support of the Pawsey Supercomputing Centre including expert support from Dr Marco De La Pierre, supercomputing application specialist, the collaborating groups have been able to refine a large library of small molecules to a selection of a few compounds which they will investigate further by both computer simulations and wet-lab experiments.

The project collaboration leads are Dr Tom Karagiannis from the Department of Diabetes, Monash University and Dr Andrew Hung at RMIT University. They have been granted two hundred thousand service units on Topaz GPU cluster, a new commodity Linux cluster, supporting pre- and post-processing of data, throughput workflows, and simulations.

The expert support being provided by Dr Marco De La Pierre is enabling them to run an accelerated analysis on a novel architecture.

Dr Karagiannis said, "The COVID-19 coronavirus is like a really nasty cold - they are in the same virus family. Coronaviruses are a moving target because of their mutation rate. Most researchers are focussing on surface proteins, i.e. the spike protein of the coronavirus which has a strong affinity for angiotensin-converting enzyme 2 (ACE2) receptors - distributed throughout our lungs, cardiovascular system, kidney and intestines - and the nucleocapsid protein, both of which are thought to be important for eliciting an immune response. A vaccine will ultimately be against these types of surface proteins; but these proteins are the ones that usually mutate, rendering vaccines ineffective.

"What we're doing is focusing on the main protease which is highly conserved among human coronaviruses."

Earlier this year Dr Karagiannis's team in collaboration with Dr Andrew Hung received an allocation on a Magnus supercomputer as part of the National Merit Allocation Scheme (meritorious access to a national computation infrastructure across Australia) to investigate chronic pain.

See also the Pawsey Supercomputing Centre 21 April announcement