Improved docking, screening and selectivity prediction for small molecule nuclear receptor modulators using conformational ensembles

Nuclear receptors (NRs) are ligand dependent transcriptional factors and play a key role in reproduction, development, and homeostasis of organism. NRs are potential targets for treatment of cancer and other diseases such as inflammatory diseases, and diabetes. In this study, we present a comprehensive library of pocket conformational ensembles of thirteen human nuclear receptors (NRs), and test the ability of these ensembles to recognize their ligands in virtual screening, as well as predict their binding geometry, functional type, and relative binding affinity. 157 known NR modulators and 66 structures were used as a benchmark. Our pocket ensemble library correctly predicted the ligand binding poses in 94% of the cases. The models were also highly selective for the active ligands in virtual screening, with the areas under the ROC curves ranging from 82 to a remarkable 99%. Using the computationally determined receptor-specific binding energy offsets, we showed that the ensembles can be used for predicting selectivity profiles of NR ligands. Our results evaluate and demonstrate the advantages of using receptor ensembles for compound docking, screening, and profiling.

[1]  Peter I Bonta,et al.  NR4A nuclear receptors in atherosclerosis and vein-graft disease. , 2007, Trends in cardiovascular medicine.

[2]  R. Bouillon,et al.  Structure-function relationships in the vitamin D endocrine system. , 1995, Endocrine reviews.

[3]  Gerhard Klebe,et al.  Molecular Docking Screens Using Comparative Models of Proteins , 2009, J. Chem. Inf. Model..

[4]  Michael J. Keiser,et al.  Predicting new molecular targets for known drugs , 2009, Nature.

[5]  R. Abagyan,et al.  Flexible ligand docking to multiple receptor conformations: a practical alternative. , 2008, Current opinion in structural biology.

[6]  C. Q. Lee,et al.  The Computer Journal , 1958, Nature.

[7]  D. Newling,et al.  Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer. , 2001, Urology.

[8]  M. Redinbo,et al.  Orphan nuclear receptors adopted by crystallography. , 2005, Current opinion in structural biology.

[9]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[10]  Dino Moras,et al.  Ligand binding domain of vitamin D receptors. , 2006, Current topics in medicinal chemistry.

[11]  Kendall W Nettles,et al.  Ligand control of coregulator recruitment to nuclear receptors. , 2005, Annual review of physiology.

[12]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

[13]  Sean Ekins,et al.  PXR and the regulation of apoA1 and HDL-cholesterol in rodents. , 2004, Pharmacological research.

[14]  R. Abagyan,et al.  Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. , 1994, Journal of molecular biology.

[15]  E C Dees,et al.  Recent advances in systemic therapy for breast cancer , 1998, Current opinion in oncology.

[16]  H. Samuels,et al.  Nuclear hormone receptor coregulator: role in hormone action, metabolism, growth, and development. , 2005, Endocrine reviews.

[17]  M Carlquist,et al.  Structure of the ligand‐binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist , 1999, The EMBO journal.

[18]  Kaori Fukuzawa,et al.  Molecular interactions between estrogen receptor and its ligand studied by the ab initio fragment molecular orbital method. , 2006, The journal of physical chemistry. B.

[19]  P. Sigler,et al.  Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. , 2000, Science.

[20]  R Abagyan,et al.  Flexible protein–ligand docking by global energy optimization in internal coordinates , 1997, Proteins.

[21]  Chris P. Miller,et al.  Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. , 2001, Journal of medicinal chemistry.

[22]  John A. Nelder,et al.  A Simplex Method for Function Minimization , 1965, Comput. J..

[23]  B. O’Malley,et al.  Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. , 1995, Genes & development.

[24]  S. Srivastava,et al.  Androgen receptor mutation (T877A) promotes prostate cancer cell growth and cell survival , 2006, Oncogene.

[25]  Ruben Abagyan,et al.  Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Maxim Totrov,et al.  Atomic Property Fields: Generalized 3D Pharmacophoric Potential for Automated Ligand Superposition, Pharmacophore Elucidation and 3D QSAR , 2007, Chemical biology & drug design.

[27]  Ruben Abagyan,et al.  ICM—A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation , 1994, J. Comput. Chem..

[28]  R Abagyan,et al.  Rational discovery of novel nuclear hormone receptor antagonists , 2000, Proc. Natl. Acad. Sci. USA.

[29]  H. Gronemeyer,et al.  Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications. , 2000, Trends in pharmacological sciences.

[30]  Takeshi Ishikawa,et al.  Ab initio fragment molecular orbital study of molecular interactions in liganded retinoid X receptor: specification of residues associated with ligand inducible information transmission. , 2008, The journal of physical chemistry. B.

[31]  Philippe Kastner,et al.  Nonsteroid nuclear receptors: What Are genetic studies telling us about their role in real life? , 1995, Cell.

[32]  Kaori Fukuzawa,et al.  Ab initio fragment molecular orbital study of molecular interactions between liganded retinoid X receptor and its coactivator; part II: influence of mutations in transcriptional activation function 2 activating domain core on the molecular interactions. , 2008, The journal of physical chemistry. A.

[33]  Ruben Abagyan,et al.  In silico discovery of novel Retinoic Acid Receptor agonist structures , 2001, BMC Structural Biology.

[34]  Ruben Abagyan,et al.  Four-dimensional docking: a fast and accurate account of discrete receptor flexibility in ligand docking. , 2009, Journal of medicinal chemistry.

[35]  Duane D. Miller,et al.  Structural basis for antagonism and resistance of bicalutamide in prostate cancer , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Ruben Abagyan,et al.  Prediction of the binding energy for small molecules, peptides and proteins , 1999, Journal of molecular recognition : JMR.

[37]  A. Badenoch Urology , 1934, Glasgow Medical Journal.

[38]  M. Quinkler,et al.  Enzyme-mediated protection of the mineralocorticoid receptor against progesterone in the human kidney , 2001, Molecular and Cellular Endocrinology.

[39]  R. Evans,et al.  Nuclear receptors and lipid physiology: opening the X-files. , 2001, Science.

[40]  J. Pascussi,et al.  The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. , 2008, Annual review of pharmacology and toxicology.

[41]  B. Pitt,et al.  The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. , 1999, The New England journal of medicine.

[42]  R Abagyan,et al.  Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs , 2007, Proceedings of the National Academy of Sciences.

[43]  Paul Webb,et al.  Conformational adaptation of nuclear receptor ligand binding domains to agonists: Potential for novel approaches to ligand design , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[44]  Olivier Sperandio,et al.  Receptor-based computational screening of compound databases: the main docking-scoring engines. , 2006, Current protein & peptide science.

[45]  B. Smith,et al.  Determinants of spironolactone binding specificity in the mineralocorticoid receptor. , 2003, Journal of molecular endocrinology.

[46]  R. Abagyan,et al.  Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states. , 2008, Journal of medicinal chemistry.