@article{34a0d930977c47ebb626ff5b8bd8a876,
title = "Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations",
abstract = "Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N-[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank. As the docking poses obtained in the virtual screening pipeline did not align with the experimental cocrystal structures, we evaluated the predictions of their precise binding modes by performing molecular dynamics (MD) simulations. The MD simulations closely reproduced the experimentally observed protein-ligand cocrystal binding conformations and interactions for all compounds. These results suggest a computational workflow to generate experimental-quality protein-ligand binding models, overcoming limitations of docking results due to receptor flexibility and incomplete sampling, as a useful starting point for the structure-based lead optimization of novel BRD4(BD1) inhibitors.",
author = "Allen, {Bryce K.} and Saurabh Mehta and Ember, {Stuart W.J.} and Zhu, {Jin Yi} and Ernst Sch{\"o}nbrunn and Ayad, {Nagi G.} and Sch{\"u}rer, {Stephan C.}",
note = "Funding Information: *E-mail: sschurer@miami.edu, sschurer@med.miami.edu (S.C.S.). ORCID Saurabh Mehta: 0000-0002-9174-128X Stephan C. Sch{\"u}rer: 0000-0001-7180-0978 Author Contributions B.K.A. and S.M. performed computational modeling, molecular dynamics, data curation, and data integration; B.K.A. developed code and performed biological experiments. S.W.J.E., J.-Y.Z., and E.S. conducted X-ray diffraction and DSF experiments. B.K.A. and S.C.S. performed data analysis. S.C.S. designed the study, and S.C.S. and N.G.A. advised the project. B.K.A., S.W.J.E., S.M., and S.C.S. wrote the manuscript. All authors contributed to and reviewed the manuscript. Funding This work was in part supported by grants U54CA189205 (Illuminating the Druggable Genome Knowledge Management Center, IDG-KMC) and U54HL127624 (BD2K LINCS Data Coordination and Integration Center, DCIC). The IDG-KMC is a component of the Illuminating the Druggable Genome (IDG) project (https://commonfund.nih.gov/idg) awarded by the NCI. The BD2K LINC DCIC is awarded by the National Heart, Lung, and Blood Institute through funds provided by the trans-NIH Library of Integrated Network-based Cellular Signatures (LINCS) Program (http://www.lincsproject.org/) and the trans-NIH Big Data to Knowledge (BD2K) initiative (http://www.bd2k.nih.gov). Both IDG and LINCS are NIH Common Fund projects. This work was in part supported by NS067289 to NGA. Notes The authors declare no competing financial interest. Funding Information: The authors would like to thank ChemAxon for providing the academic research license for their Cheminformatics software tools including JChem for Excel and the Marvin tools. The authors thank D. E. Shaw Research and Schr{\"o}dinger for the Molecular Dynamics (MD) simulation package and Open Eye Scientific Software for their academic research licenses. S.M. gratefully acknowledges the receipt of CREST fellowship award (BT/IN/DBT-CREST Awards/29/SM/2012-13) from the Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India. S.C.S. acknowledges computational resources of the Drug Discovery program of the Center for Computational Science at the University of Miami. The authors thank the Moffitt Structural Biology Core for use of the X-ray crystallography facility.",
year = "2017",
doi = "10.1021/acsomega.7b00553",
language = "English (US)",
volume = "2",
pages = "4760--4771",
journal = "ACS Omega",
issn = "2470-1343",
publisher = "American Chemical Society",
number = "8",
}