Abstract:

Respiratory viruses such as human rhinovirus (HRV), influenza, and respiratory syncytial virus (RSV) are leading causes of global illness, particularly a ecting vulnerable populations. Despite their impact on morbidity and mortality, antiviral treatment options remain limited and increasing drug-resistant viral strains emerge. Studies suggest that Ltype calcium channel blockers (CCBs), commonly prescribed for cardiovascular conditions, may inhibit viral replication by disrupting calcium ion homeostasis, a process critical to the viral replication cycle. This undergraduate thesis investigates the repurposing potential of CCBs, particularly amlodipine and its derivatives (“AMP” compounds), as antiviral agents through structure-based virtual screening (SBVS).

The initial phase (Jan-Nov 2024) focused on HRV-16, targeting the VP1 capsid protein (PDB: 1ND3) using Schrödinger software. A receptor grid was developed based on the known HRV inhibitor pleconaril. CCBs and AMP compounds docked with scores comparable to pleconaril, and seven top candidates were identified for potential therapeutic development.

Building on these findings, the second phase (Spring 2025) extended the screening to the neuraminidase (NA) protein of influenza (PDB: 2HT7, 4KS5) and the fusion (F) protein of RSV (PDB: 6VKD, 7KQD). AMP compounds docked with stronger scores than known active ligands at the NA active site, and docking scores significantly correlated with in vitro inhibition for the 2HT7 grid (p=0.0011). QSAR analysis predicted favorable drug-like properties of AMP compounds. Enrichment performance was assessed using active compounds and DUD-E generated decoys on the 2HT7 grid, demonstrating modest discrimination between actives and decoys (ROC AUC=0.61), and limited early enrichment (RIE=0.54). Docking to RSV F protein models showed no significant correlation with biological activity, however, AMP ligands docked with scores rivaling those of known active ligands.

This research highlights the potential of repurposing L-type CCBs as broad-spectrum antivirals. These findings support a novel antiviral strategy leveraging existing drug sca olds to address critical gaps in respiratory virus therapeutics.

Speaker:

Aiden T. Day, Saint Joseph’s College of Maine

Aiden T. Day is a recent graduate of Saint Joseph’s College of Maine, where he earned a Bachelor of Science in Medical Biology/Pre-Medicine with a minor in Chemistry. He is an aspiring surgeon-scientist with a deep commitment to advancing patient care through translational research. His academic and research background spans medicinal chemistry, public health, and neurosurgery.