Citation:
Thesis Type:
PhD ThesisAbstract:
The process of discovering a new drug is always evolving with the knowledge, technologies, and needs of the time. This information should be used to guide your search and to separate legitimate drug candidates from artifacts and suboptimal leads. In fact, it has been said that a Drug Hunter’s job is not to find the best molecule, but to find a reason why every molecule is not the best molecule. The focus of this dissertation is firstly the application of computational drug discovery and repurposing to identify new treatments for diseases. Secondly, it is the mechanistic understanding of two artifacts common in early-stage drug discovery and repurposing that if used appropriately, should remove potential false-positive screening hits from being pursued as lead candidates.
Chapter 1 describes the large-scale docking technology developed in the lab and how it can be used to discover new drugs for protein targets of interest to a particular disease. It further describes the utility of drug repurposing and how it was used during the COVID-19 pandemic to search for novel antivirals. Briefly, it introduces how ligands discovered in drug repurposing screens were ultimately found to be acting through mechanisms that confounded their antiviral activities.
Chapter 2 demonstrates how compounds that induce a phenomenon known as drug-induced phospholipidosis are not legitimate antivirals, and that this effect is a confound in cell-based antiviral repurposing screens. This shared mechanism underlies the activity of many σ1 and σ2 ligands, among others, that were pursued as potential antivirals early in the COVID-19 pandemic. Counter-screening for this activity will help save time, money, and resources from being spent on drugs that have no legitimate promise as antiviral drugs.
Chapter 3 identifies colloidal aggregation as another mechanism by which many compounds show up as false-positive screening hits in biochemical drug repurposing screens. Importantly, we demonstrate that by reducing the formation of colloids in screening assays, we can remove false-positive enzymatic activity of multiple ligands that otherwise appear to be inhibitors of viral proteins.
Chapter 4 demonstrates a legitimate use for σ2 ligands as potential therapeutics, importantly controlling for both phospholipidosis and aggregation as confounding factors in their activity. We demonstrate with novel selective ligands that σ2 receptor ligands are antiallodynic in neuropathic pain models, and that their effects are time-dependent, replicating similar phenotypes of other σ2 ligands from the literature.
Chapter 5 applies the large-scale docking technique on the lipid-binding G-protein coupled cannabinoid-1 (CB1) receptor. Here, we demonstrate the concept of “new chemistry for new biology” by first identifying a novel CB1 agonist and then finding that it has strongly analgesic properties but lacks two of the major cannabinoid side-effects: sedation and catalepsy.