TY - JOUR
T1 - Optimization of inhibitors of Mycobacterium tuberculosis pantothenate synthetase based on group efficiency analysis
AU - Hung, Alvin W.
AU - Silvestre, H. Leonardo
AU - Wen, Shijun
AU - George, Guillaume P. C.
AU - Boland, Jennifer
AU - Blundell, Tom L.
AU - Ciulli, Alessio
AU - Abell, Chris
N1 - © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
PY - 2016/1/5
Y1 - 2016/1/5
N2 - Ligand efficiency has proven to be a valuable concept for optimization of leads in the early stages of drug design. Taking this one step further, group efficiency (GE) evaluates the binding efficiency of each appendage of a molecule, further fine-tuning the drug design process. Here, GE analysis is used to systematically improve the potency of inhibitors of Mycobacterium tuberculosis pantothenate synthetase, an important target in tuberculosis therapy. Binding efficiencies were found to be distributed unevenly within a lead molecule derived using a fragment-based approach. Substitution of the less efficient parts of the molecule allowed systematic development of more potent compounds. This method of dissecting and analyzing different groups within a molecule offers a rational and general way of carrying out lead optimization, with potential broad application within drug discovery.
AB - Ligand efficiency has proven to be a valuable concept for optimization of leads in the early stages of drug design. Taking this one step further, group efficiency (GE) evaluates the binding efficiency of each appendage of a molecule, further fine-tuning the drug design process. Here, GE analysis is used to systematically improve the potency of inhibitors of Mycobacterium tuberculosis pantothenate synthetase, an important target in tuberculosis therapy. Binding efficiencies were found to be distributed unevenly within a lead molecule derived using a fragment-based approach. Substitution of the less efficient parts of the molecule allowed systematic development of more potent compounds. This method of dissecting and analyzing different groups within a molecule offers a rational and general way of carrying out lead optimization, with potential broad application within drug discovery.
U2 - 10.1002/cmdc.201500414
DO - 10.1002/cmdc.201500414
M3 - Article
C2 - 26486566
SN - 1860-7179
VL - 11
SP - 38
EP - 42
JO - ChemMedChem
JF - ChemMedChem
IS - 1
ER -