Aravindhan and Subha at their computers working on research

Professors Aravindhan Ganesan (Pharmacy, left) and Subha Kalyaanamoorthy (Chemistry, right) use drug design methods to target the molecular machinery that supports COVID-19 replication.

To effectively design treatment for a virus, scientists must first understand its structure and dynamics at the molecular level. COVID-19, which is caused by the SARS-CoV-2 virus, is no exception, and has been the object of intense study by scientists around the world over the last year. 

Aravindhan Ganesan, a pharmacy professor, and Subha Kalyaanamoorthy, a chemistry professor, are two of these scientists. The husband-and-wife team are new to the University of Waterloo, joining just months before COVID-19 sent students and faculty alike to remote learning and working.  In a recent publication, they showed how drug design methods can be refined to target the main protease, or Mpro , a part SARS-CoV-2 which contributes to viral replication.

“Despite working from home, we knew we’d be able to conduct research to support the global fight against COVID-19,” says Ganesan. “We identified important physical aspects of the SARS-CoV-2 Mpro structure so that we’d have a better idea of how to design effective drugs to treat the disease.”

Since their research relies on computer analysis, both professors adapted their experiments to keep them running outside the lab, at home. Ganesan specializes in molecular modelling and simulation, and Kalyaanamoorthy is an expert in bioinformatics and drug design.

Together, they ventured on examining more than hundred structures of fragment-bound SARS-CoV-2 Mpro complexes.

“From previous research, we know that Mproplays a critical role in how the virus replicates itself and spreads,” says Kalyaanamoorthy. “Targeting it with drug therapy might enable us to stop the virus from replicating. Mprois also a druggable target, meaning it has pockets that can easily be targeted by small molecule drugs. This is critical: there are other important parts of the virus that could be studied, but if they can’t be effectively targeted by medication, there’s less reason to conduct further study.”

The researchers hope that understanding Mpro’s physical properties will help in responding to future pandemics as well. In 2003, Canada was hit with the SARS virus. This virus, SARS-CoV-1, was a precursor to the SARS-CoV-2 present today.

“We learned a lot from the SARS outbreak, and although there are differences between SARS-CoV-1 and SARS-CoV-2, we noticed that the Mpro – the main protease – is highly conserved across the known coronaviruses,” says Ganesan. “The hope is that by understanding Mpro, we identify a viable target for treatments not just of COVID-19 but of future viruses in the SARS-CoV family.”

The team had identified a viable target for treatment. Next, they had to identify a site on the Mpro that medication can attach to.. To find this ideal site, Ganesan and Kalyaanamoorthy’s teams, which included undergraduate students, performed robust structural analyses using molecular simulation on Mpro. They identified promising areas on the SARS-CoV-2 Mpro for enhancing the stability and affinity of the drugs binding to it.

“Specifically, we identified a lateral pocket that was partially hidden near the binding site of the Mpro,” says Ganesan. “Our simulation showed that the ligands – molecules that bind to proteins – engaging with this pocket could stay attached to the protein for quite some time as opposed to the others not interacting with the pocket. This is an ideal characteristic, as it means that drug molecules could adhere to this pocket on the Mpro for some time, allowing medication to take effect.”

A 3D rendering of several small molecule-bound Mpro structures overlapped over each other

A 3D rendering of several small molecule-bound Mpro structures overlapped over each other.

They highlighted additional qualities about this lateral pocket, identifying important characteristics that can inform drug design. However, designing a new drug is both costly and time-consuming. To use resources efficiently, Kalyaanamoorthy and Ganesan are now extending their study to examine the molecular structures of existing medications and to see if any drugs that are approved and already in circulation can be used to target the COVID-19 Mpro.

“There are thousands of drugs that could potentially be used to target the Mpro, so to narrow down our search, we’ll be using machine learning,” Kalyaanamoorthy says. “My lab has developed a sophisticated tool combining our own machine learning method and an advanced computer-aided drug design approaches to identify possible drugs against SARS-CoV-2 Mpro. We have discovered a few drugs that can affix to the lateral pocket on the SARS-CoV-2 Mpro that are currently being tested in wet lab.”

So far, the results have been promising and the researchers look forward to continuing their contributions to the fight against COVID.

“We owe our success to how much research is already out there,” says Ganesan. “What the scientific community has collectively accomplished in such a short amount of time is impressive, and we’re humbled to contribute to that.”

The study was published in the Nature Scientific Reports journal and the research teams received support from the CFREF-Transformational Quantum Technologies and the Centre for Biotechnology and Bioengineering, out of the University of Waterloo.