TY - JOUR
T1 - Retrospective mapping of SAR data for TTR protein in chemico-biological space using ligand efficiency indices as a guide to drug discovery strategies
AU - Blasi, Daniel
AU - Arsequell, Gemma
AU - Valencia, Gregori
AU - Nieto, Joan
AU - Planas, Antoni
AU - Pinto, Marta
AU - Centeno, Nuria B.
AU - Abad-Zapatero, Cele
AU - Quintana, Jordi
PY - 2011/3/23
Y1 - 2011/3/23
N2 - 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.
AB - 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.
KW - Amyloid
KW - Chemico-biological space
KW - Ligand efficiency indices
KW - TTR
UR - http://www.scopus.com/inward/record.url?scp=79958844315&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000288861600010&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1002/minf.201000157
DO - 10.1002/minf.201000157
M3 - Article
C2 - 27466770
AN - SCOPUS:79958844315
SN - 1868-1743
VL - 30
SP - 161
EP - 167
JO - Molecular Informatics
JF - Molecular Informatics
IS - 2-3
T2 - 18th European Symposium on Quantitative Structure-Activity Relationships, (EUROQUSAR’2010), Rhodes (Grecia), Setiembre 2010
Y2 - 19 September 2010 through 24 September 2010
ER -