In-Silico Discovery of Small-Molecule Snake Anti-Venoms: Prospects for Re-purposing FDA-Approved Dru

Ridgway, Harry

Institute for Sustainable Industries and Livable Cities

Victoria University

Melbourne, Australia

ridgway@vtc.net

Orry,Andrew

MolSoft, LLC

San Diego, CA, USA

While snake-bite envenomation is relatively rare in the US, the potential health effects can be serious and long-lasting, including chronic neurological dysfunctions and risk of necrotizing infections, possibly leading to fatality. Immunological (anti-venom) approaches continue to be the prescribed therapy for treating poisonous snake bites. Disadvantages of immunotherapies include: (1) the high cost of anti-venom production, and (2) reduced access to immediate treatment in many rural areas where most snake bites occur. A promising alternative to conventional anti-venom treatment is onsite administration of stable small-molecule drugs that can (in theory) be produced relatively inexpensively and readily deployed in rural areas. Discovery and development of such drugs by pharmaceutical companies and university research laboratories has been the subject of considerable investigation over the past several decades. Though generally promising, this approach has been hindered by the high cost of de-novo drug design and protracted regulatory approval combined with a low return on investment (due to low demand). One strategy that has been explored in recent years to circumvent the above marketplace and regulatory barriers is the application of bioinformatics and computer-aided drug discovery (CADD) to identify medications already approved for human use by the US Food and Drug Administration (FDA) that also show potential for re-purposing as snake-venom antagonists. We have recently employed this strategy for several venom components of the western diamondback rattlesnake Crotalus atrox, including: (1) several metalloproteinase and hemorrhagic toxins, such as Atrolysins-c/d; and (2) neuro-inflammatory acidic phospholipase A2s (snPLA2s). Results of virtual ligand screening (VLS) studies in which the active sites of the above (and related) modeled protein targets were challenged with a database of drugs approved by the FDA since 1939 yielded several promising candidate compounds that exhibited tight-binding to the target receptor catalytic sites. These molecules therefore could be explored further in laboratory bioassays and their FDA approvals possibly accelerated as repositioned drugs for snake bite envenomation.