Dataset Information

Identification of an Indazole-Based Pharmacophore for the Inhibition of FGFR Kinases Using Fragment-Led de Novo Design.

ABSTRACT: Structure-based drug design (SBDD) has become a powerful tool utilized by medicinal chemists to rationally guide the drug discovery process. Herein, we describe the use of SPROUT, a de novo-based program, to identify an indazole-based pharmacophore for the inhibition of fibroblast growth factor receptor (FGFR) kinases, which are validated targets for cancer therapy. Hit identification using SPROUT yielded 6-phenylindole as a small fragment predicted to bind to FGFR1. With the aid of docking models, several modifications to the indole were made to optimize the fragment to an indazole-containing pharmacophore, leading to a library of compounds containing 23 derivatives. Biological evaluation revealed that these indazole-containing fragments inhibited FGFR1-3 in the range of 0.8-90 ?M with excellent ligand efficiencies of 0.30-0.48. Some compounds exhibited moderate selectivity toward individual FGFRs, indicating that further optimization using SBDD may lead to potent and selective inhibitors of the FGFR family.

SUBMITTER: Turner LD

PROVIDER: S-EPMC5733262 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of an Indazole-Based Pharmacophore for the Inhibition of FGFR Kinases Using Fragment-Led <i>de Novo</i> Design.

Turner Lewis D LD Summers Abbey J AJ Johnson Laura O LO Knowles Margaret A MA Fishwick Colin W G CWG

ACS medicinal chemistry letters 20171111 12

Structure-based drug design (SBDD) has become a powerful tool utilized by medicinal chemists to rationally guide the drug discovery process. Herein, we describe the use of SPROUT, a <i>de novo</i>-based program, to identify an indazole-based pharmacophore for the inhibition of fibroblast growth factor receptor (FGFR) kinases, which are validated targets for cancer therapy. Hit identification using SPROUT yielded 6-phenylindole as a small fragment predicted to bind to FGFR1. With the aid of docki ...[more]

PMID: 29259745

Similar Datasets

Project description:We have previously reported the development and evaluation of a computational program to assist in the design of hydrophobic cores of proteins. In an effort to investigate the role of core packing in protein structure, we have used this program, referred to as Repacking of Cores (ROC), to design several variants of the protein ubiquitin. Nine ubiquitin variants containing from three to eight hydrophobic core mutations were constructed, purified, and characterized in terms of their stability and their ability to adopt a uniquely folded native-like conformation. In general, designed ubiquitin variants are more stable than control variants in which the hydrophobic core was chosen randomly. However, in contrast to previous results with 434 cro, all designs are destabilized relative to the wild-type (WT) protein. This raises the possibility that beta-sheet structures have more stringent packing requirements than alpha-helical proteins. A more striking observation is that all variants, including random controls, adopt fairly well-defined conformations, regardless of their stability. This result supports conclusions from the cro studies that non-core residues contribute significantly to the conformational uniqueness of these proteins while core packing largely affects protein stability and has less impact on the nature or uniqueness of the fold. Concurrent with the above work, we used stability data on the nine ubiquitin variants to evaluate and improve the predictive ability of our core packing algorithm. Additional versions of the program were generated that differ in potential function parameters and sampling of side chain conformers. Reasonable correlations between experimental and predicted stabilities suggest the program will be useful in future studies to design variants with stabilities closer to that of the native protein. Taken together, the present study provides further clarification of the role of specific packing interactions in protein structure and stability, and demonstrates the benefit of using systematic computational methods to predict core packing arrangements for the design of proteins.

Dataset Information

Identification of an Indazole-Based Pharmacophore for the Inhibition of FGFR Kinases Using Fragment-Led de Novo Design.

Publications

Identification of an Indazole-Based Pharmacophore for the Inhibition of FGFR Kinases Using Fragment-Led <i>de Novo</i> Design.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets