Bioinformatics Approach to Identify Non-Peptide Drugs that Mimic Heloderma suspectum Exendin-4 Activ

Ridgway, Harry ISILC – Victoria University Melbourne, Australia

AquaMem Consultants Rodeo, New Mexico, USA ridgway@vtc.net

Orry, Andrew Molsoft, LLC San Diego, California, USA

Venoms of Beaded Lizards and the Gila Monster (Helodermatidae) are complex mixtures of biotoxic proteins and polypeptides used in defense and subduing prey. Some of the major bioactive venom components include kallikrein activities (serine-protease-like enzymes) that potentiate hypotension and vascular permeation via fibrinogen degradation and tissue destruction. Kallikreins also stimulate inflammation and desquamtion (skin breakdown) related to cleavage of cellular adhesion proteins. Other important helodermatid biotoxin activities include: (1) Type III Phospholipase-A2 (PLA2) that inhibits platelet aggregation via the epinephrine-induced pathway; (2) hyaluronidase “spreading factors”; (3) “cysteine-rich secretory proteins” (CRiSPs) mediating paralysis of peripheral smooth muscle and induction of hypothermia via blockage of various transport channels, including ryanodine and L-type calcium channels; (4) B-type natriuretic peptides and helokinestatin precursor peptides (antagonists of bradykinin at the B2 bradykinin receptor) that invoke hypotension through the relaxation of aortic smooth muscle; and (5) xendins which induces hypotension via relaxation of cardiac smooth muscle. Exendin-4, isolated from H. suspectum venom, is a short peptide agonist of the glucagon-like protein-1 receptor (GLP-1R) that promotes insulin secretion in pancreatic beta-cells. In this respect, exendin-4 mimics the activity of the endogenous glucagon-like peptide-1 (GLP-1). In 2005, exendin-4 (exenitide, under the trade name Byetta) was approved by the FDA for clinical treatment to enhance plasma insulin secretion in type 2 diabetics. The aim of our research is to identify (and ultimately repurpose) already FDA-approved or experimental-phase non-peptide drugs that mimic or otherwise enhance the activity of exendin-4 and/or the endogenous GLP-1 peptide. To achieve this goal, we make use of a combination of chem/bioinformatics, molecular dynamics, and virtual ligand screening (VLS) to identify drugs that exhibit favorable target GLP-1 receptor binding characteristics in silico. Preliminary results from this research will be presented and discussed at the conference.