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Accelerating Drug Discovery and Repurposing by Combining Transcriptional Signature Connectivity with Docking [article]

Alexander W Thorman, James Reigle, Somchai Chutipongtanate, Behrouz Shamsaei, Marcin Pilarczyk, Mehdi Fazel-Najafabadi, Rafal Adamczak, Michal Kouril, Ardythe L Morrow, Maria F Czyzyk-Krzeska, Robert McCullumsmith, William Seibel (+6 others)
2020 bioRxiv   pre-print
The development of targeted treatment options for precision medicine is hampered by a slow and costly process of drug screening. While small molecule docking simulations are often applied in conjunction with cheminformatic methods to reduce the number of candidate molecules to be tested experimentally, the current approaches suffer from high false positive rates and are computationally expensive. Here, we present a novel in silico approach for drug discovery and repurposing, dubbed connectivity
more » ... enhanced Structure Activity Relationship (ceSAR) that improves on current methods by combining docking and virtual screening approaches with pharmacogenomics and transcriptional signature connectivity analysis. ceSAR builds on the landmark LINCS library of transcriptional signatures of over 20,000 drug-like molecules and ~5,000 gene knock-downs (KDs) to connect small molecules and their potential targets. For a set of candidate molecules and specific target gene, candidate molecules are first ranked by chemical similarity to their concordant LINCS analogs that share signature similarity with a knock-down of the target gene. An efficient method for chemical similarity search, optimized for sparse binary fingerprints of chemical moieties, is used to enable fast searches for large libraries of small molecules. A small subset of candidate compounds identified in the first step is then re-scored by combining signature connectivity with docking simulations. On a set of 20 DUD-E benchmark targets with LINCS KDs, the consensus approach reduces significantly false positive rates, improving the median precision 3-fold over docking methods at the extreme library reduction. We conclude that signature connectivity and docking provide complementary signals, offering an avenue to improve the accuracy of virtual screening while reducing run times by multiple orders of magnitude.
doi:10.1101/2020.11.25.399238 fatcat:g6hynweebnc3di4ysq53j6mkde

Biases in the Experimental Annotations of Protein Function and Their Effect on Our Understanding of Protein Function Space

Alexandra M. Schnoes, David C. Ream, Alexander W. Thorman, Patricia C. Babbitt, Iddo Friedberg, Christine A. Orengo
2013 PLoS Computational Biology  
The ongoing functional annotation of proteins relies upon the work of curators to capture experimental findings from scientific literature and apply them to protein sequence and structure data. However, with the increasing use of high-throughput experimental assays, a small number of experimental studies dominate the functional protein annotations collected in databases. Here we investigate just how prevalent is the "few articles -- many proteins" phenomenon. We examine the experimentally
more » ... ted annotation of proteins provided by several groups in the GO Consortium, and show that the distribution of proteins per published study is exponential, with 0.14% of articles providing the source of annotations for 25% of the proteins in the UniProt-GOA compilation. Since each of the dominant articles describes the use of an assay that can find only one function or a small group of functions, this leads to substantial biases in what we know about the function of many proteins. Mass-spectrometry, microscopy and RNAi experiments dominate high throughput experiments. Consequently, the functional information derived from these experiments is mostly of the subcellular location of proteins, and of the participation of proteins in embryonic developmental pathways. For some organisms, the information provided by different studies overlap by a large amount. We also show that the information provided by high throughput experiments is less specific than those provided by low throughput experiments. Given the experimental techniques available, certain biases in protein function annotation due to high-throughput experiments are unavoidable. Knowing that these biases exist and understanding their characteristics and extent is important for database curators, developers of function annotation programs, and anyone who uses protein function annotation data to plan experiments.
doi:10.1371/journal.pcbi.1003063 pmid:23737737 pmcid:PMC3667760 fatcat:dyez23i4n5hxjbh3lctoen3uvi

Page 457 of National Union Catalog Vol. 19, Issue [page]

1948 National Union Catalog  
Pewter 739.23 NK7210 TS 50-5385 Edgar, pseud. see MacDowell, Edward Alexander, 1361-1908 Thorn, Eduard, 1887- ed.  ...  Mental physiology and hygiene. 1 Tit RC605.T45 1950 616.8 51-1316 Thorman, Henriette Elisabeth see Thorman, Elisabeth, 1867- Thormann, Karl Friedrich.  ... 

Page 804 of American Society for Microbiology. ASM News Vol. 39, Issue 12 [page]

1973 American Society for Microbiology. ASM News  
BLAND, JEANNE ALEXANDER, and RICHARD 5S. HANSON. Dept. of Bacteriol., Univ. of Wiscon- sin, Madison. Differentiation of Selected Species of Arthro- bacter by Reactions on Dye-Containing Media.  ...  W. BERNLOHR. Department of Microbiology, Uni- versity of Minnesota, Minneapolis. Calcium Dipicolinate and Heat Resistance of Bacterial Spores. R. S. HANSON.  ... 

Page 502 of Journal of Bone and Joint Surgery Vol. 34A, Issue 2 [page]

1952 Journal of Bone and Joint Surgery  
., Denver, Colorado Alexander Hersh, M.D., New York, N. ¥ Robert P. Holt, M.D., San Antonio, Texas Jim M.  ...  Rohrbaugh, Jr., M.D., Chevy Chase, Marvland Robert Manser Rose, M.D., New Orleans, Louisiana Robert Thorman Rosenfeld, M.D., Beverly Hills, California Stuart Wells Russell, M.D., Hanover, New Hampshire  ... 

Page 54 of Florida Bar Journal Vol. 20, Issue 2 [page]

1946 Florida Bar Journal  
THORMAN of Cleveland, Ohio. W. W.  ...  WATSON, RAY W.  ... 

Page 31 of Journal of Marital and Family Therapy Vol. 6, Issue 3 [page]

1980 Journal of Marital and Family Therapy  
Thomas, Alexander and Chess, Stella. The Dynamics of Psychological Development. New York: Brunner/Mazel, 1980. Thorman, George. Family Violence. Illinois: Charles C. Thomas, 1980.  ...  Across the Editor’s Desk* Books Received Coan, Richard W. Psychologists. New York: Irvington Publishers, Inc., 1979. Cohen, Sara Kay. Whoever Said Life Is Fair? New York: Charles Schribner’s, 1980.  ... 

Page 41 of Journal of the American Ceramic Society Vol. 10, Issue 1 [page]

1927 Journal of the American Ceramic Society  
NEW MEMBERS RECEIVED FROM NOVEMBER 15 TO DECEMBER 16, Horace W. Alexander, student, 412 E. Green St., Champaign, III. Rebecca G. Allen, 132 Marlborough St., Boston, Mass. Oscar L.  ...  Thorman, 1 P. . Tillotson, 1 P . W. Tillotson, 1 P., 1 C /. E. S. Turner, 2 P. “Twells, 2P. J. Vachuska, 1 P. . H. Vaughn, 2 P. S. Watts, 4 P. Wilson, 4 P. G. Wolfram, 1 P. . G. Worcester, 1 P. . H.  ... 

Page 410 of Ohio History Vol. 45, Issue 4 [page]

1936 Ohio History  
Thompson, eo 4 Thompson, Thompson, Villian Oxley Thorman, Simson Thorn, Isaac Thornton, Mrs. Elizabeth C. Kenton, Kenton, Elizabeth C. Thornton, Madison Thrall, O. M.  ...  N. 178 Thwaites, Reuben Gold—Early Western Travels 7 Tiffin, wz -82, 71, 72, 81, 86, 301, = Tod, David W. Toledo, O., 299, 300, 301, 302, 306, 307, '308, ‘818, 316, "317, 319.  ... 

Page 197 of The Solicitors' Journal Vol. 57, Issue 12 [page]

1913 The Solicitors' Journal  
, dec Thorman v Speed to vary certificate (Thomas’ claim) In re Alexander, dec v Speed to vary (Bowyer Lane’s claim) n re Pickering’s Settlement Pickering v Forster adjd sumns In re Beaumont, dec Bradshaw  ...  Bassett’s Estate and In re the Settled Land Acts, 1882 to 1890 adjd sumns adjd sumns In re W Gillett, dec Woolley adjd sumns In re Alexander Tod, dec shaw v Tod adjd sumns In re Smith, dec Chambers v Wallace  ... 

Page 552 of Florida Bar Journal Vol. 34, Issue 8 [page]

1960 Florida Bar Journal  
THOMPSON* PERCY WALTER THOMPSON* ROBERT S THOMPSON* WARNER PAUL THOMPSON* william earl THOMSON* ADDISON H THOMSON* DAVID M THOMSON* GEORGE BAKER THOMSON* JOHN M THOMSON* MElDRIM JR THOMSON* ROBERT MILLER THORMAN  ...  HUGH ARTHUR THORNTON* H VINCENT THORNTON* JOHN wIlLIAM THORNTON* RICHARD JOSEPH THREADGILL* ROBERT H THURLOW* THOMAS H TIETIG* EDWARD CHESTER TILLETT* BOONE D JR TILLIS* MONTE J JR TILLOTSON* STEPHEN ALEXANDER  ... 

Page 16 of Journal of the American Podiatric Medical Association Vol. 9, Issue 9 [page]

1919 Journal of the American Podiatric Medical Association  
Harmolin, Cleveland; W. M. Stone, A. . Thorman, Cincinnati; A. D. Shaw, Dayton. Oklahoma—W. M. Chadwick, Okla. City. Pennsylvania—M. S. Gabell, Hazelton; J. R. Bennie, Wm. Bedell, Philadelphia; E. J.  ...  Alexander, E. S. Wahman, St. Paul; M. Cc. Rew, M. A. Braley, F. E. Cornwell, Mankato; D. G. Lindblad. ‘Crookstor; B. F. Kenison, Duluth. Nebraska—H. W. Weeks, I. Ryley, Helen Ryley, Omaha.  ... 

Page 387 of Journal of Marriage and Family Vol. 14, Issue 4 [page]

1952 Journal of Marriage and Family  
W., Else Frenkel-Brunswick, J. J. Levin- son, and R. N. Sanford Authoritarian Personality Melvin Seeman 14:83-84 Alexander, Franz, M.D.  ...  4:82; 5:65; 7:58; 8:61 Terman, Lewis M. 12:51 Thorman, George D. 14:23 Thorpe, Alice G. 13:104-105 ff.  ... 

Page 497 of RIBA [Royal Institute of British Architects] Journal Vol. 13, Issue 17 [page]

1906 RIBA [Royal Institute of British Architects] Journal  
W. G. A. Hambling). WILSON: Herbert; Bromfield Terrace, Tadcaster Masters : Messrs. Bromet & Thorman WOOD: Wallace; “ The Lindens,’’ West Bromwich, near Birmingham [ Masters : Messrs.  ...  W. W. Robinson}. BRYAN: Arthur Francis {Probationer 1902|; c/o W. M. Cowdell, 12 Grey Friars, Leicester [Master : Mr. W. M. Cowdell }.  ... 

Page 731 of Florida Bar Journal Vol. 33, Issue 8 [page]

1959 Florida Bar Journal  
PERCY WALTER THOMPSON* ROBERT S THOMPSON* WARNER PAUL THOMPSON* WILLIAM EARL THOMSON* ADDISON H THOMSON* DAVID M THOMSON* GEORGE BAKER THOMSON* JOHN MILLER THOMSON* MELDRIM JR THOMSON* ROBERT MILLER THORMAN  ...  THORNBURG* HUGH ARTHUR THORNTON* H VINCENT THORNTON* JOHN WILLIAM THORNTON* RICHARD JOSEPH THREAOGILL* ROBERT H THUE* MONRAD R JR THURLOW* THOMAS H TILLETT* BOONE D jR TILLIS* monte j JR TILLOTSON* STEPHEN ALEXANDER  ... 
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