How “Docking Software” Helped Discover Compounds That Could Boost Stroke, TBI Recovery

Using the University of Florida’s HiPerGator supercomputer with the University of California San Francisco’s DOCK software, researchers have identified two dipeptides as small molecule activators of the peptidase neurolysin enzyme.

Render of peptidase neurolysin enzyme.

Peptidase neurolysin is an enzyme that has been found to be “one of the brain’s potent, self-protective mechanisms promoting preservation and recovery of the brain after acute injury” (Karamyan). Karamyan’s research posited that in the case of these injuries, neurolysin is responsible for:

  • reducing fluid buildup around the brain (cerebral edema)
  • reducing neural cell death caused by excess neurotransmitters (excitotoxicity)
  • reducing inflammatory response in the brain (neuroinflammation)

Searching for ways to make neurolysin more effective, lead researcher Vardan Karamyan, PhD (Texas Tech University Health Sciences Center Department of Pharmaceutical Sciences) enlisted the help of David Ostrov, PhD (University of Florida College of Medicine Department of Pathology, Immunology and Laboratory Medicine).

Neurolysin is similar in structure to a molecule called ACE2 (angiotensin converting enzyme-2), the main receptor for the virus that causes COVID. Dr. Ostrov previously identified drugs that bind ACE2, and he used the same strategy to identify drug candidates that bind neurolysin.

Superposition of neurolysin (copper) on ACE2 (teal).

Ostrov used UF’s HiPerGator supercomputer to screen 139,725 compounds from a repository at the National Cancer Institute Developmental Therapeutics Program to identify candidates that could fit a site on neurolysin that would facilitate an increase in the enzyme’s function. This was achieved using the DOCK program package, developed by UCSF.

DOCK’s molecular docking simulations were used to identify if and how a ligand (drug-like small molecule) can bind to the active site of a macromolecule (in this case, neurolysin). This is usually done to find ways to promote or inhibit a macromolecule’s function, making molecular docking software a key component in the ever-expanding world of computational drug discovery.

According to the UFHealth Newsroom, UF’s HiPerGator supercomputer completed the query in 15 hours–only 1.4% of the time it would take a desktop computer to complete the same task.

In the lab, the researchers tested the function of DOCK’s best matches on rat neurolysin. They found that the dipeptides L-histidlyl-L-tyrosine and L-histidlyl-L-histidine enhanced the activity of neurolysin.

According to Ostrov, human clinical trials with the mentioned drug candidates could begin within 2 years if FDA approved drugs are found to enhance neurolysin activity. An approved drug could assist or facilitate recovery in stroke and traumatic brain injury (TBI) patients.

This article is based on the following sources

– Bennett, D. (2021, September 7). UF health researcher, collaborators discover compounds that might boost stroke recovery. University of Florida Health.
– Karamyan, V. T. (2019, October). Peptidase neurolysin is an endogenous cerebroprotective mechanism in acute neurodegenerative disorders.
– Statements from David A. Ostrov, PhD (University of Florida College of Medicine, Department of Pathology, Immunology and Laboratory Medicine)