By Judith Van Dongen, originally published via WSU Spokane Research News
Looking for a change after completing his undergraduate degree in chemistry, Chris Szlenk left his home state of Alabama in 2017 to pursue a PhD at Washington State University’s College of Pharmacy and Pharmaceutical Sciences. A rotation in the lab of assistant professor Senthil Natesan got him interested in the field of computer-aided drug design. Szlenk’s research in that area recently got him honored as a highlighted trainee author in the October 2021 issue of the journal Molecular Pharmacology.
What exactly is computer-aided drug design?
Drug design as a process is expensive and time-consuming and the number of drugs failing in clinical trials is extremely high. Computer-aided drug design allows you to simulate molecules and their respective proteins, as well as their environment—such as water and cell membranes—at an atomistic level. You can think of it as a computational microscope. You can look at the atom-by-atom level to see how things are interacting with each other and then use that information to develop molecules that better interact with their particular receptor target or with the environment around them. Running these simulations prior to doing any clinical trials can help save money, time, and effort in the long run.
What got you interested in this field of research?
When I came to WSU, I was interested in how drugs interact in the body. I didn’t necessarily want to do wet lab work—I was much more interested in visualizing at an atomistic level what’s going on with a drug, like how a molecule binds to the receptor. I only became exposed to the concept of computer-aided drug design when I sat down for interviews to pick a mentor here. When I met my current mentor—Dr. Senthil Natesan—basically everything he explained was what I’ve always wanted to do. So, I decided to do my first rotation in his lab and just fell in love with it and was able to stay on.
What type of research do you do within the field of computer-aided drug design?
Our lab is focused on how we can use the cell membrane in a rational manner. The cell membrane is on the surface of any cell and is a very complex mixture of lipids—or fat molecules—along with other components. A lot of proteins are actually embedded across this membrane that separates the outer and inner layer of the cell. We’re interested in how a drug gets to its particular target by using that membrane interaction. This is one reason why I study membrane-embedded proteins. The other reason is that the majority of FDA-approved drugs bind to these membrane-embedded targets, so it’s important to get more information on how that process happens.
What are some recent research projects you’ve worked on?
I had a recent publication about beta-2 adrenergic receptors. Drugs that are used for the treatment of asthma and chronic obstructive pulmonary disorder (COPD) target and activate that receptor. Experimental results from other research groups showed that there’s a membrane interaction that affects how quickly these drugs get to their target. Basically, it affects the onset of action for some drugs and might also be implicated in their duration of action. In my paper I described in detail how that process happens, which helps to explain why some drugs have quick onset of action and a short duration of action, while others have slower onset but a longer duration of action.
I also study the mu-opioid receptor, which is targeted by opiates, or pain-relieving medications. The reason we’re looking at that is to see whether we can design a molecule that binds in the transmembrane region of the receptor and still gives you the benefits of common opioids but with fewer negative side effects, so that your breathing rate isn’t affected, you don’t get as much constipation, and your tolerance doesn’t build up as quickly as with common opiates. In that case you could perhaps use a smaller dose of an opiate with that molecule to reduce overdose potential.
Two other membrane-embedded proteins I’ve worked with are the GABA subtype A receptor—which facilitates binding of anti-anxiety medication such as Xanax and Valium—and resolvins, which are molecules that help fight inflammation in the body. That last project might eventually prove helpful in the development of therapeutics for treating inflammation.
What is your proudest achievement so far?
I’ve published four papers and was first author on three of them. I’m particularly proud of the fact that people have read those papers, synthesized the information, and thought they were relevant enough to cite in their own papers.
What do you hope to see come out of your work in the long run?
The ultimate goal would be for this work to lead to improved therapeutics with limited negative side effects, a better understanding of how drugs actually get to their particular target, and the ability to design molecules that use these drug-membrane interactions in a rational manner.
Besides research and classes, what has kept you busy here at WSU?
I served as vice president of the Graduate Research Student Association and PhD senator for the Associated Students of Washington State University Health Sciences (ASWSUHS) last year and was vice president of the Health Sciences Student Advocacy Association for three years. I was also selected as a 2020 Washington Fellow for the American Society of Pharmacology and Experimental Therapeutics (ASPET), which allowed me to go lobby for science funding to our state senators.
When will you graduate, and what’s next for you?
I’m defending my dissertation this coming March. After I graduate, I hope to land a job working in research and development for a pharmaceutical company.
Do you want to give a shout-out to anyone who has helped you succeed?
I want to thank my mentor, Dr. Senthil Natesan, who has given me the opportunity to really dive into the issues and difficult questions and let my curiosity guide me. My graduate student cohort and my wife have also been really supportive.
This interview has been edited and condensed for clarity.