AI is a viable alternative to high throughput screening: a 318-target study.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

High-Throughput Screening Assays*/methods ; Drug Discovery*/methods; Small Molecule Libraries/pharmacology ; Small Molecule Libraries/chemistry

High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery.
(© 2024. The Author(s).)

Erratum in: Sci Rep. 2024 Sep 16;14(1):21579. doi: 10.1038/s41598-024-70321-w. (PMID: 39284864)

J Biomol Screen. 1999;4(2):67-73. (PMID: 10838414)
Nat Rev Drug Discov. 2022 Mar;21(3):181-200. (PMID: 35042991)
Nat Biotechnol. 2020 Feb;38(2):143-145. (PMID: 32001834)
J Comput Aided Mol Des. 1998 Sep;12(5):471-90. (PMID: 9834908)
Chem Sci. 2023 Jan 10;14(6):1443-1452. (PMID: 36794205)
J Chem Inf Model. 2019 Mar 25;59(3):1253-1268. (PMID: 30615828)
J Biomol Screen. 2006 Apr;11(3):247-52. (PMID: 16490779)
J Chem Inf Comput Sci. 2004 Jan-Feb;44(1):170-8. (PMID: 14741025)
Nature. 2009 Nov 12;462(7270):175-81. (PMID: 19881490)
Virol J. 2020 Jul 30;17(1):116. (PMID: 32727587)
J Med Chem. 2010 Apr 8;53(7):2719-40. (PMID: 20131845)
J Chem Inf Model. 2015 Feb 23;55(2):263-74. (PMID: 25635324)
J Chem Inf Comput Sci. 2003 Nov-Dec;43(6):1947-58. (PMID: 14632445)
J Med Chem. 2020 Aug 27;63(16):8857-8866. (PMID: 32525674)
Nat Rev Drug Discov. 2003 Apr;2(4):259-66. (PMID: 12669025)
J Med Chem. 2010 Apr 8;53(7):2986-97. (PMID: 20235539)
ACS Med Chem Lett. 2023 Mar 16;14(4):466-472. (PMID: 37077402)
iScience. 2022 Mar 26;25(4):104170. (PMID: 35465359)
Signal Transduct Target Ther. 2020 Sep 23;5(1):213. (PMID: 32968059)
Bioorg Med Chem Lett. 2013 May 1;23(9):2688-91. (PMID: 23522563)
Science. 2023 Mar 3;379(6635):939-945. (PMID: 36862767)
BMC Bioinformatics. 2009 Jun 02;10:168. (PMID: 19486540)
Adv Sci (Weinh). 2021 Jul;8(14):e2004846. (PMID: 34060252)
Int J Mol Sci. 2022 Mar 14;23(6):. (PMID: 35328548)
J Med Chem. 2002 Apr 11;45(8):1712-22. (PMID: 11931626)
Commun Biol. 2021 Sep 9;4(1):1050. (PMID: 34504303)
J Mol Model. 2007 Aug;13(8):897-905. (PMID: 17487515)
Science. 2018 Nov 16;362(6416):. (PMID: 30442776)
Chem Soc Rev. 2020 Jun 7;49(11):3525-3564. (PMID: 32356548)
Nature. 2004 Dec 16;432(7019):862-5. (PMID: 15602552)
ChemMedChem. 2022 Aug 17;17(16):e202200278. (PMID: 35726731)
PLoS One. 2019 Aug 20;14(8):e0220113. (PMID: 31430292)
Nature. 2019 Feb;566(7743):224-229. (PMID: 30728502)
J Biol Chem. 2020 Sep 25;295(39):13516-13531. (PMID: 32723867)
iScience. 2020 Oct 15;23(11):101681. (PMID: 33145486)
J Chem Inf Model. 2020 Nov 23;60(11):5457-5474. (PMID: 32813975)
Curr Top Med Chem. 2005;5(4):397-411. (PMID: 15892682)
Nat Rev Drug Discov. 2012 Mar 01;11(3):191-200. (PMID: 22378269)
J Med Chem. 2018 Nov 8;61(21):9442-9468. (PMID: 29920198)
J Med Chem. 2022 Feb 24;65(4):3606-3615. (PMID: 35138850)
Nat Rev Drug Discov. 2011 Mar;10(3):188-95. (PMID: 21358738)
J Med Chem. 2023 Jun 8;66(11):7101-7139. (PMID: 37224022)
J Comput Chem. 2011 Jan 15;32(1):81-98. (PMID: 20607693)
J Comput Chem. 2010 Jan 30;31(2):455-61. (PMID: 19499576)
Curr Top Med Chem. 2005;5(8):751-62. (PMID: 16101415)
Nature. 2022 Jan;601(7893):452-459. (PMID: 34912117)
Methods Mol Biol. 2009;575:249-79. (PMID: 19727619)
J Med Chem. 2020 Aug 27;63(16):8867-8875. (PMID: 32787146)
Cell Metab. 2019 Dec 3;30(6):1131-1140.e7. (PMID: 31564441)
Science. 1992 Aug 21;257(5073):1078-82. (PMID: 1509259)
J Chem Inf Model. 2018 May 29;58(5):916-932. (PMID: 29698607)
Nat Chem Biol. 2005 Aug;1(3):146-8. (PMID: 16408018)
Nat Rev Drug Discov. 2002 Nov;1(11):882-94. (PMID: 12415248)
Drug Discov Today Technol. 2006 Winter;3(4):405-411. (PMID: 38620182)
Cell. 2020 Feb 20;180(4):688-702.e13. (PMID: 32084340)
J Chem Inf Model. 2022 Mar 14;62(5):1178-1189. (PMID: 35235748)
ACS Chem Biol. 2012 Aug 17;7(8):1429-35. (PMID: 22625864)
J Chem Inf Model. 2010 May 24;50(5):742-54. (PMID: 20426451)
Drug Discov Today Technol. 2019 Dec;32-33:9-17. (PMID: 33386100)
Nat Rev Drug Discov. 2004 Nov;3(11):935-49. (PMID: 15520816)
J Chem Inf Model. 2017 Aug 28;57(8):2077-2088. (PMID: 28651433)
J Biomol Screen. 2006 Oct;11(7):864-9. (PMID: 16973922)
J Med Chem. 2022 Jan 27;65(2):1458-1480. (PMID: 34726887)
J Med Chem. 2010 Jan 14;53(1):37-51. (PMID: 19908840)
J Chem Inf Model. 2020 Apr 27;60(4):1969-1982. (PMID: 32207612)
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3583-7. (PMID: 8475107)
Nat Biotechnol. 2006 Feb;24(2):167-75. (PMID: 16465162)
Nat Chem Biol. 2007 Aug;3(8):466-79. (PMID: 17637779)
ACS Cent Sci. 2018 Nov 28;4(11):1520-1530. (PMID: 30555904)
Nat Rev Drug Discov. 2022 Oct;21(10):736-762. (PMID: 35941229)
Trends Pharmacol Sci. 2022 Jan;43(1):4-15. (PMID: 34782164)
J Cheminform. 2013 May 30;5(1):26. (PMID: 23721588)
J Comput Aided Mol Des. 2019 Jan;33(1):1-18. (PMID: 30632055)
J Chem Inf Model. 2022 Feb 14;62(3):553-566. (PMID: 35050621)
Curr Protoc Chem Biol. 2012;4:177-191. (PMID: 26705509)
J Med Chem. 2012 Nov 26;55(22):9763-72. (PMID: 23061697)
J Chem Inf Model. 2014 Oct 27;54(10):2807-15. (PMID: 25207678)
Nat Biotechnol. 2019 Sep;37(9):1038-1040. (PMID: 31477924)

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0 (Small Molecule Libraries)

Date Created: 20240402 Date Completed: 20240404 Latest Revision: 20241126

20241202

PMC10987645

10.1038/s41598-024-54655-z

38565852