title: Design of e-pharmacophore models using compound fragments for the trans-sialidase of Trypanosoma cruzi: screening for novel inhibitor scaffolds.
abstract: Chagas' is a fatal disease that affects millions of people worldwide. The lack of safe and effective treatments for Chagas' highlights the need for the discovery of new drugs to fight the disease. Trypanosoma cruzi, the parasitic cause of Chagas' disease, synthesizes a trans-sialidase (TcTS) enzyme responsible for the transfer of sialic acids from the host cell surface to glycoconjugates on the parasitic cell surface. TcTS has no human analogs and is vital to the life cycle of T. cruzi, making TcTS an important enzyme for drug design against Chagas' disease. We use fragment docking to generate various e-pharmacophore hypotheses depicting protein residues important for ligand binding. Virtual screening of the ZINC Clean Leads database with more than 4 million compounds using the e-pharmacophore models found 82 potential inhibitors of TcTS. Molecular dynamics and free energy of binding calculations were used to rank the compounds based on their affinity for TcTS. Two compounds-ZINC13359679 and ZINC02576132-were found to be the most promising lead candidates for TcTS inhibition, and their binding modes are analyzed in detail.
authors.affiliation: Department of Chemistry, Quantum Theory Project, University of Florida, Gainesville, FL 32611-7200, USA.
authors.forename: Bill R
authors.initials: BR
authors.lastname: Miller
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Roitberg
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009439:Neuraminidase / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D014349:Trypanosoma cruzi / Q000201:enzymology
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D006023:Glycoproteins; C069715:trans-sialidase; D009439:Neuraminidase
keywords: Docking; MM-GBSA; Molecular dynamics; Pharmacophore; trans-Sialidase