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Retrospective Mapping of SAR Data for TTR Protein in Chemico‐Biological Space Using Ligand Efficiency Indices as a Guide to Drug Discovery Strategies
Author(s) -
Blasi Daniel,
Arsequell Gemma,
Valencia Gregori,
Nieto Joan,
Planas Antoni,
Pinto Marta,
Centeno Nuria B.,
AbadZapatero Cele,
Quintana Jordi
Publication year - 2011
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201000157
Subject(s) - ligand efficiency , transthyretin , quantitative structure–activity relationship , ligand (biochemistry) , drug discovery , chemistry , chemical space , drug , computational biology , representation (politics) , computer science , combinatorial chemistry , pharmacology , biochemistry , stereochemistry , medicine , biology , receptor , politics , political science , law
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 ( LEI s). 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.