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. Our findings suggest that the antagonist compounds antagonize FGF23 through the disruption of protein-protein interactions between FGF23 and fibroblast growth factor receptor (FGFR).

Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface

“…By accounting for the conformational diversity of the receptor ensemble docking enhances the likelihood of identifying predicted hits (enrichment), which may be lost when screening against a single conformation of the target 12 . We have previously applied this technique to derive experimentally-verified hits for several protein targets to treat diseases ranging from bacterial infections to osteoporosis [14][15][16][17][18][19][20][21][22] . For this work three phases of calculations were performed: structural modeling, molecular simulations (ensemble building), and small-molecule docking (in silico ligand screening)…”

A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

“…When multiple co-crystallized structures of a protein are available with different bound ligands, docking of each bound ligand to the other co-crystal structures (or grids of the other co-crystallized structures) is generally described as cross docking [ 28 , 29 , 30 , 31 , 32 ]. The cross docking experiments were carried out to evaluate the selectivity of various binding sites.…”

Repurposing Therapeutics for the Wuhan Coronavirus nCov-2019: Supercomputer-Based Docking to the Viral S Protein and Human ACE2 Interface

“…By accounting for the conformational diversity of the receptor ensemble docking enhances the likelihood of identifying predicted hits (enrichment), which may be lost when screening against a single configuration 9 . We have previously applied this technique to derive experimentallyverified hits for several protein targets [11][12][13][14][15][16][17][18][19] . Briefly, the work reported here was performed in three phases: structural modeling, molecular simulations (ensemble building), and smallmolecule docking (in silico ligand screening)…”