title: In Silico Aptamer Docking Studies: From a Retrospective Validation to a Prospective Case Study-TIM3 Aptamers Binding.
abstract: Complementing Systematic Evolution of Ligands by EXponential Enrichment (SELEX) technologies with in silico prediction of aptamer binders has attracted a lot of interest in the recent years. We propose a workflow involving 2D structure prediction, 3D RNA modeling using Rosetta and docking to the target protein with 3dRPC for: (i) prediction of the binding mode of our two previously reported potent (Kd < 50 nmol/l) murine TIM3 aptamers, and (ii) the prioritization of TIM3 aptamers that were enriched in the SELEX workflow. The procedure was first validated in five different study cases. As a novelty, cluster analysis of the docked poses was carried out and shown to be useful in reproducing the binding mode or at least in identifying the binding site and the experimental aptamer-protein interactions. For TIM3, our therapeutic target of interest, a plausible binding site and binding mode was identified that might explain the lack of cross-reactivity in murine over human TIM-3. Concerning the prioritization of the aptamers, the inclusion of the cluster analysis as an additional criterion following a rank-by-rank approach is discussed and compared with the performance of the docking scoring function alone for two validation cases and for the prospective assessment of the novel aptamers as TIM3 binders.
authors.affiliation: Small Molecule Discovery Platform, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Obdulia
authors.initials: O
authors.lastname: Rabal
authors.affiliation: Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Aptamers Unit, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pastor
authors.affiliation: Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Aptamers Unit, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Villanueva
authors.affiliation: Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Aptamers Unit, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Mario M
authors.initials: MM
authors.lastname: Soldevilla
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.|Program Immunology and Immunotherapy, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervas-Stubbs
authors.affiliation: Small Molecule Discovery Platform, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal