title: Retrospective Mapping of SAR Data for TTR Protein in Chemico-Biological Space Using Ligand Efficiency Indices as a Guide to Drug Discovery Strategies.
abstract: We have previously reported the design and synthesis of ligands that stabilize Transthyretin protein (TTR) in order to obtain therapeutically active compounds for Familial Amyloid Polyneuropathy (FAP). We are hereby reporting a drug design strategy to optimize these ligands and map them in Chemico-Biological Space (CBS) using Ligand Efficiency Indices (LEIs). We use a binding efficiency index (BEI) based on the measured binding affinity related to the molecular weight (MW) of the compound combined with surface-binding efficiency index (SEI) based on Polar Surface Area (PSA). We will illustrate the use of these indices, combining three crucial variables (potency, MW and PSA) in a 2D graphical representation of chemical space, to perform a retrospective mapping of SAR data for a current TTR inhibitors database, and we propose prospective strategies to use these efficiency indices and chemico-biological space maps for optimization and drug design efforts for TTR ligands.
authors.affiliation: Drug Discovery Platform, Parc Científic Barcelona (PCB), Baldiri Reixac 4-6, E-08028 Barcelona, Spain. dblasip@pcb.ub.es.
authors.forename: Daniel
authors.initials: D
authors.lastname: Blasi
authors.affiliation: Unit of Glycoconjugate Chemistry, Institut de Química Avançada de Catalunya, I.Q.A.C.-C.S.I.C., Jordi Girona 18-26, E-08034 Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Arsequell
authors.affiliation: Unit of Glycoconjugate Chemistry, Institut de Química Avançada de Catalunya, I.Q.A.C.-C.S.I.C., Jordi Girona 18-26, E-08034 Barcelona, Spain.
authors.forename: Gregori
authors.initials: G
authors.lastname: Valencia
authors.affiliation: Laboratory of Biochemistry, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Nieto
authors.affiliation: Laboratory of Biochemistry, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Planas
authors.affiliation: Computer-Assisted Drug Design Laboratory, Research Group on Biomedical Informatics (GRIB), IMIM-Universitat Pompeu Fabra, Dr. Aiguader 88, E-08003 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pinto
authors.affiliation: Computer-Assisted Drug Design Laboratory, Research Group on Biomedical Informatics (GRIB), IMIM-Universitat Pompeu Fabra, Dr. Aiguader 88, E-08003 Barcelona, Spain.
authors.forename: Nuria B
authors.initials: NB
authors.lastname: Centeno
authors.affiliation: Drug Discovery Platform, Parc Científic Barcelona (PCB), Baldiri Reixac 4-6, E-08028 Barcelona, Spain.|Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 So. Ashland St, MBRB Building, Room 3020; (M/C870), Chicago, IL 60607-7173, USA.
authors.forename: Cele
authors.initials: C
authors.lastname: Abad-Zapatero
authors.affiliation: Drug Discovery Platform, Parc Científic Barcelona (PCB), Baldiri Reixac 4-6, E-08028 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Quintana
keywords: Amyloid; Chemico-biological space; Ligand efficiency indices; TTR