Retrospective Mapping of SAR Data for TTR Protein in Chemico-Biological Space Using Ligand Efficiency Indices as a Guide to Drug Discovery Strategies

Daniel Blasi; Gemma Arsequell; Gregori Valencia; Joan Nieto; Antoni Planas; Marta Pinto; Nuria B Centeno; Cele Abad-Zapatero; Jordi Quintana

doi:10.1002/minf.201000157

Retrospective Mapping of SAR Data for TTR Protein in Chemico-Biological Space Using Ligand Efficiency Indices as a Guide to Drug Discovery Strategies

Mol Inform. 2011 Mar 14;30(2-3):161-7. doi: 10.1002/minf.201000157. Epub 2011 Mar 18.

Authors

Daniel Blasi¹, Gemma Arsequell², Gregori Valencia², Joan Nieto³, Antoni Planas³, Marta Pinto⁴, Nuria B Centeno⁴, Cele Abad-Zapatero^{5

6}, Jordi Quintana⁵

Affiliations

¹ Drug Discovery Platform, Parc Científic Barcelona (PCB), Baldiri Reixac 4-6, E-08028 Barcelona, Spain. dblasip@pcb.ub.es.
² 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.
³ Laboratory of Biochemistry, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain.
⁴ Computer-Assisted Drug Design Laboratory, Research Group on Biomedical Informatics (GRIB), IMIM-Universitat Pompeu Fabra, Dr. Aiguader 88, E-08003 Barcelona, Spain.
⁵ Drug Discovery Platform, Parc Científic Barcelona (PCB), Baldiri Reixac 4-6, E-08028 Barcelona, Spain.
⁶ Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 So. Ashland St, MBRB Building, Room 3020; (M/C870), Chicago, IL 60607-7173, USA.

PMID: 27466770
DOI: 10.1002/minf.201000157

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.

Keywords: Amyloid; Chemico-biological space; Ligand efficiency indices; TTR.