The coronavirus pandemic has killed more than 1.14 million people globally since China reported its first case to the World Health Organization (WHO) in December. According to the latest numbers, the United States has more than 8.46 million cases and 223,000 deaths. As scientists around the world are racing to develop a vaccine, a 14-year-old girl from Frisco, Texas may have found a potential solution.
On October 13, eighth-grade student Anika Chebrolu won the 2020 3M Young Scientist Challenge in an interactive virtual event that showcased inventors demonstrating innovative thinking, scientific acumen and display of exceptional communication skills. Chebrolu’s project used in-silico methodology to identify a lead molecule that can selectively bind to the spike protein of the SARS-CoV-2 virus. In winning the annual innovation competition, Chebrolu received a $25,000 cash prize, the prestigious title of “America’s Top Young Scientist”, and a destination trip.
Chebrolu was also selected as a recipient of the competition’s Improving Lives Award through a public voting process that recognized one project with the potential to change the most lives.
“I am extremely humbled at being selected America’s Top Young Scientist as all of the finalists had amazing projects and were extremely well-rounded individuals,” said Chebrolu. “Science is the basis of life and the entire universe and we have a long way to go to understand it fully.”
What is In-Silico Methodology?
The term ‘in silico’ is derived from the computer component silicium; in-silico methods, therefore, refer to the use of computational approaches. According to Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays, in-silico modeling can be effective in the speedy evaluation of a drug’s toxicological risk, helping to reduce time and cost in the early stages of the drug development process.
Not only can in-silico methods make fast predictions for a large set of compounds in high-throughput mode, these simulations can be conducted based on the structure of a compound even before it has been synthesized. As a result, compounds can be built in cases where they may not originally have been available.
When designing new drugs, scientists often perform computational studies as a critical first step. Use of in-silico models combines the advantages of both in-vivo and in-vitro experimentation in a practical manner, as researchers have the opportunity to assess a virtually unlimited array of parameters. To date, in-silico techniques have contributed to developments in congenital heart surgery, obstetric anaesthesia airway management, mechanical ventilation and cardiopulmonary bypass/ventricular support devices.
Targeting the SARS-CoV-2 Spike Protein
The SARS-CoV-2 spike (S) protein is a structure that juts off the coronavirus surface and penetrates into human cells to trigger infection. Each S protein targets and binds to the host receptor angiotensin-converting enzyme 2 (ACE2), eventually fusing into the cell membrane and replicating. By mediating cell attachment and entry of the virus into the host cell, the spike protein plays an essential role in the viral infectivity of COVID-19. The average SARS-CoV-2 particle has about 90 spike trimers.
Chebrolu’s research involved using numerous software tools to screen millions of molecules and narrow her search down to one lead molecule that would specifically bind to the COVID-19 S protein, effectively inhibiting it. Starting out with a database of over 698 million compounds, Chebrolu used in-silico methodology to assess molecules for their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, along with their binding affinities, molecular structure and drug-like characteristics (such as how they would break down in the human body and whether they could be toxic to cells). At the end of the iterative screening process, Chebrolu finally singled out the (5E)-1-(3-Fluorophenyl)-5-[(2E)-3-(2-furyl)-2-propen-1-ylidene]-2-thioxodihydro-4,6(1H,5H)-pyrimidinedione ligand for blocking the function of the spike protein—preventing the virus from infecting cells and thereby creating a viable drug target.
It Started with the Flu
Chebrolu’s project was not originally focused on finding a solution for the COVID-19 pandemic. When she first entered the Young Scientist Challenge, it was to find an effective cure for the influenza virus—after having suffered a severe bout of the infection the previous year.
“Even with the antivirals that we have, even with the annual vaccination and even with our constant fight with the influenza virus, there’s still [tens of thousands of] deaths annually in the U.S. alone because of the flu,” emphasized Chebrolu in an interview. “So I started my research on drug discovery and the influenza virus—and I ended up combining my knowledge of both of these subjects to create a novel antiviral drug against the flu.”
After the pandemic hit, Chebrolu changed her scope of work to target the SARS-CoV-2 virus because of the drastic impact that it had made on the world in such a short amount of time.
“After spending so much time researching about pandemics, viruses and drug discovery, it was crazy to think that I was actually living through something like this,” expressed Chebrolu.
With the help of her mentor, Dr. Mahfuza Ali (a 3M corporate scientist in the materials resource division), Chebrolu translated her influenza-based in-silico methodology to tackle the SARS-CoV-2 virus.
According to Chebrolu’s YouTube video, the hemagglutinin protein is responsible for facilitating the entry of the influenza virus into host cells (much like the S protein of the SARS-CoV-2 virus), and is thus a promising drug target.
To prepare the hemagglutinin protein for screening, Chebrolu first had to identify the best binding site on the hemagglutinin protein. She downloaded the protein from the RCSB PDB database, which contains tools and resources for research in molecular biology, structural biology and computational biology. Chebrolu used the FT map computational mapping web tool to determine that the S1 site was the best druggable hotspot on the hemagglutinin protein.
As a next step, Chebrolu obtained 3D structures of all drug-like molecules from the ZINC-15 small molecule database. Chebrolu screened three million small molecules through Lipinski’s Rule of 5—a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would make it a likely orally active drug in humans.
Lipinski’s rule states that, in general, an orally active drug should have no more than one violation of the following criteria:
- No more than 5 hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds).
- No more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms).
- A molecular mass less than 500 daltons.
- An octanol-water partition coefficient (log P) that does not exceed 5.
(The rule is named based on its quoted numbers all being multiples of five.)
Approximately 250,000 molecules passed the Lipinski’s Rule of 5 screening. Chebrolu subjected these to an initial molecular docking test by using the CLC Drug Discovery Workbench software to find the top 100 molecules with the highest binding affinity to the given druggable binding site on the hemagglutinin protein.
Chebrolu then used the admetSAR 2.0 web tool to test the top 100 molecules for ADMET properties. Only six molecules passed, which were subsequently put through a more comprehensive and thorough binding energy test using the AutoDock program in PyRx software. Out of the initial three million compounds, a lead molecule was finally declared with a superior binding affinity of –8.2 kCal per molecule, thus narrowing down a potential drug candidate that could selectively bind and inhibit the hemagglutinin protein of the influenza virus and be further developed as an antiviral drug for the treatment of influenza.
Chebrolu’s Future Prospects
Previous winners of the 3M Young Scientist Challenge have gone on to give TED Talks, file patents, found nonprofits, make the Forbes 30-Under-30 list, ring the bell at the New York Stock Exchange, and exhibit at the White House Science Fair. These young innovators have also been featured in The New York Times Magazine, Forbes, Business Insider, and on national television programs such as Good Morning America and The Ellen DeGeneres Show.
Chebrolu says that while the title of Top Young Scientist is an honor, she isn’t quite done yet. She plans to work alongside scientists and researchers to conduct in-vitro and in-vivo testing of her lead drug candidate in order to develop her findings into an actual cure for the virus.
“My effort to find a lead compound to bind to the spike protein of the SARS-CoV-2 virus this summer may appear to be a drop in the ocean, but still adds to all these efforts,” says Chebrolu. “How I develop this molecule further with the help of virologists and drug development specialists will determine the success of these efforts.”
As for her prize money, Chebrolu plans to donate some of her winnings to a nonprofit she created over the summer called Academy Aid. The charity helps other young students pursuing STEM research.
“I know that I personally was given a bunch of opportunities to pursue science and STEM but a lot of kids around the world are not given the same opportunities as me,” explains Chebrolu. “If they were, they could accomplish so much more.”
Chebrolu also plans to put some of her money toward continuing her research to develop her antiviral compound into an effective and potent drug. In 15 years’ time, she hopes to be a medical researcher and professor.
“My grandpa, when I was younger, he used to always push me towards science,” reminisces Chebrolu. “He was actually a chemistry professor. He used to always tell me to learn the periodic table of elements and learn all these things about science. Over time, I just grew to love it.”
The secret to Chebrolu’s success?
“Never stop asking questions,” she says. “Whenever you see an opportunity just go for it. You can do a lot if you just have confidence in yourself and believe in yourself.”
In her free time, Chebrolu trains for an Indian classical dance called Bharatanatyam, which she has been practicing for eight years. She also loves creating art and playing the guitar.
“I describe myself as a person who aspires to be a lot of things,” Chebrolu laughs. “You just have to learn to overcome challenges when they come at you. Anything is possible despite your age, no matter if you are young or old.”