Molecular Docking of Lectins and a Metalloprotease from Snake Venom with GPVI: a Basis for the Design of Antiplatelet and Antimetastatic Peptides

Protein-derived peptides are promising pharmacology tools, as they may reproduce the functional region of the original molecule with lower molecular mass, reduced immunogenicity, relatively simple synthesis, better tissue penetration and greater selectivity, overcoming limitations of intact proteins. Snake venoms are valuable sources of such models, including lectins, which recognize carbohydrates and cell receptors, and metalloproteases, zinc-dependent enzymes that act on hemostasis. The lectins neuwlectin and leuculectin purified from Bothrops neuwiedi and Bothrops leucurus venom, respectively, display antiangiogenic and antiplatelet actions. Leuc-a, a metalloprotease from B. leucurus, also shows antiplatelet potential. Binding assays showed that all three proteins bind to glycoprotein VI (GPVI), the main platelet collagen receptor, involved in platelet aggregation and tumor metastasis. To predict the binding mode and residues involved in their interaction, and thereby guide peptide design, protein-protein docking was performed using the crystal structures of GPVI (PDB 2GI7) and leuc-a (PDB 4Q1L). Neuwlectin and leuculectin structures were obtained by comparative modeling, using as templates lectins from Crotalus atrox (86.67% identity; 2.20 Å resolution) and Bothrops jararacussu (99.26% identity; 2.95 Å resolution), respectively. Docking was carried out with AlphaFold3, ClusPro and HDOCK. The AlphaFold 3 models were discarded due to low interface confidence, whereas ClusPro and HDOCK produced low-energy models with high confidence scores and populous clusters. Models from both programs converging on the same binding mode were selected: ClusPro 2 and HDOCK 3 for neuwlectin, HDOCK 1 and ClusPro 3 for leuculectin, and ClusPro 1 and HDOCK 5 for leuc-a. For neuwlectin, molecular dynamics indicated slightly greater stability for the ClusPro model 2. These models will guide peptide prediction, and the peptides will be tested in vitro and in vivo for inhibition of platelet aggregation, compared with the native proteins.