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Title: Ensemble docking to difficult targets in early-stage drug discovery: Methodology and application to fibroblast growth factor 23

Abstract

Ensemble docking is now commonly used in early-stage in silico drug discovery and can be used to attack difficult problems such as finding lead compounds which can disrupt protein–protein interactions. We give an example of this methodology here, as applied to fibroblast growth factor 23 (FGF23), a protein hormone that is responsible for regulating phosphate homeostasis. The first small-molecule antagonists of FGF23 were recently discovered by combining ensemble docking with extensive experimental target validation data (Science Signaling, 9, 2016, ra113). Here, we provide a detailed account of how ensemble-based high-throughput virtual screening was used to identify the antagonist compounds discovered in reference (Science Signaling, 9, 2016, ra113). Moreover, we perform further calculations, redocking those antagonist compounds identified in reference (Science Signaling, 9, 2016, ra113) that performed well on drug-likeness filters, to predict possible binding regions. These predicted binding modes are rescored with the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) approach to calculate the most likely binding site. Furthermore, our findings suggest that the antagonist compounds antagonize FGF23 through the disruption of protein–protein interactions between FGF23 and fibroblast growth factor receptor (FGFR).

Authors:
 [1];  [1];  [2];  [2];  [2];  [1]; ORCiD logo [1]
  1. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
  2. Univ. of Tennessee Health Science Center, Memphis, TN (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1531256
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Chemical Biology & Drug Design
Additional Journal Information:
Journal Volume: 91; Journal Issue: 2; Journal ID: ISSN 1747-0277
Publisher:
Wiley
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; 97 MATHEMATICS AND COMPUTING; ensemble docking; fibroblast growth factor; MM/PBSA; molecular dynamics

Citation Formats

Velazquez, Hector A., Riccardi, Demian, Xiao, Zhousheng, Quarles, Leigh Darryl, Yates, Charles Ryan, Baudry, Jerome Y., and Smith, Jeremy C. Ensemble docking to difficult targets in early-stage drug discovery: Methodology and application to fibroblast growth factor 23. United States: N. p., 2017. Web. doi:10.1111/cbdd.13110.
Velazquez, Hector A., Riccardi, Demian, Xiao, Zhousheng, Quarles, Leigh Darryl, Yates, Charles Ryan, Baudry, Jerome Y., & Smith, Jeremy C. Ensemble docking to difficult targets in early-stage drug discovery: Methodology and application to fibroblast growth factor 23. United States. doi:10.1111/cbdd.13110.
Velazquez, Hector A., Riccardi, Demian, Xiao, Zhousheng, Quarles, Leigh Darryl, Yates, Charles Ryan, Baudry, Jerome Y., and Smith, Jeremy C. Mon . "Ensemble docking to difficult targets in early-stage drug discovery: Methodology and application to fibroblast growth factor 23". United States. doi:10.1111/cbdd.13110. https://www.osti.gov/servlets/purl/1531256.
@article{osti_1531256,
title = {Ensemble docking to difficult targets in early-stage drug discovery: Methodology and application to fibroblast growth factor 23},
author = {Velazquez, Hector A. and Riccardi, Demian and Xiao, Zhousheng and Quarles, Leigh Darryl and Yates, Charles Ryan and Baudry, Jerome Y. and Smith, Jeremy C.},
abstractNote = {Ensemble docking is now commonly used in early-stage in silico drug discovery and can be used to attack difficult problems such as finding lead compounds which can disrupt protein–protein interactions. We give an example of this methodology here, as applied to fibroblast growth factor 23 (FGF23), a protein hormone that is responsible for regulating phosphate homeostasis. The first small-molecule antagonists of FGF23 were recently discovered by combining ensemble docking with extensive experimental target validation data (Science Signaling, 9, 2016, ra113). Here, we provide a detailed account of how ensemble-based high-throughput virtual screening was used to identify the antagonist compounds discovered in reference (Science Signaling, 9, 2016, ra113). Moreover, we perform further calculations, redocking those antagonist compounds identified in reference (Science Signaling, 9, 2016, ra113) that performed well on drug-likeness filters, to predict possible binding regions. These predicted binding modes are rescored with the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) approach to calculate the most likely binding site. Furthermore, our findings suggest that the antagonist compounds antagonize FGF23 through the disruption of protein–protein interactions between FGF23 and fibroblast growth factor receptor (FGFR).},
doi = {10.1111/cbdd.13110},
journal = {Chemical Biology & Drug Design},
number = 2,
volume = 91,
place = {United States},
year = {2017},
month = {9}
}

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