Discovery of Inhibitors of Four Bromodomains by Fragment-Anchored Ligand Docking.

Amedeo Caflisch,Andrea Dalle Vedove,Jean-Rémy Marchand,Graziano Lolli

doi:10.1021/acs.jcim.7b00336

Amedeo Caflisch, Andrea Dalle Vedove + Show 2 more

Open Access

https://doi.org/10.1021/acs.jcim.7b00336

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Abstract

The high-throughput docking protocol called ALTA-VS (anchor-based library tailoring approach for virtual screening) was developed in 2005 for the efficient in silico screening of large libraries of compounds by preselection of only those molecules that have optimal fragments (anchors) for the protein target. Here we present an updated version of ALTA-VS with a broader range of potential applications. The evaluation of binding energy makes use of a classical force field with implicit solvent in the continuum dielectric approximation. In about 2 days per protein target on a 96-core compute cluster (equipped with Xeon E3-1280 quad core processors at 2.5 GHz), the screening of a library of nearly 77 000 diverse molecules with the updated ALTA-VS protocol has resulted in the identification of 19, 3, 3, and 2 μM inhibitors of the human bromodomains ATAD2, BAZ2B, BRD4(1), and CREBBP, respectively. The success ratio (i.e., number of actives in a competition binding assay in vitro divided by the number of compounds tested) ranges from 8% to 13% in dose-response measurements. The poses predicted by fragment-based docking for the three ligands of the BAZ2B bromodomain were confirmed by protein X-ray crystallography.

Highlights

anchor-based library tailoring approach for virtual screening (ALTA-VS) was developed in 2005 for the efficient in silico screening of large libraries of compounds by preselection of only those molecules that have optimal fragments for the protein target
We make use of a transferable force field which treats in a consistent way the parameters of proteins (CHARMM36)[15] and organic compounds (CGenFF).[16,17]
Evidence has accumulated on the success of fragment−hit identification with force fieldbased approaches which make use of explicit[6] or implicit solvent treatment.[5,7−9]

Summary

Introduction

ALTA-VS (anchor-based library tailoring approach for virtual screening) was developed in 2005 for the efficient in silico screening of large libraries of compounds by preselection of only those molecules that have optimal fragments (anchors) for the protein target. The updated ALTA-VS protocol has led to the discovery of 27 small-molecule inhibitors with micromolar potency for the target bromodomain and, in particular, 15 compounds with an affinity below 100 μM.

Results

Conclusion