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McClellanville Library
Closed for renovations
Phone: (843) 887-3699
Miss Jane's Building (Edisto Library Temporary Location)
2 p.m. – 6 p.m.
Phone: (843) 869-2355
Main Library
9 a.m. - 8 p.m.
Phone: (843) 805-6930
West Ashley Library
9 a.m. - 7 p.m.
Phone: (843) 766-6635
Folly Beach Library
Closed for renovations
Phone: (843) 588-2001
John L. Dart Library
9 a.m. - 7 p.m.
Phone: (843) 722-7550
St. Paul's/Hollywood Library
9 a.m. - 8 p.m.
Phone: (843) 889-3300
Mt. Pleasant Library
9 a.m. – 8 p.m.
Phone: (843) 849-6161
Dorchester Road Library
9 a.m. - 8 p.m.
Phone: (843) 552-6466
Edgar Allan Poe/Sullivan's Island Library
9 a.m. - 1 p.m.
Phone: (843) 883-3914
John's Island Library
9 a.m. - 8 p.m.
Phone: (843) 559-1945
Wando Mount Pleasant Library
9 a.m. - 8 p.m.
Phone: (843) 805-6888
Otranto Road Library
9 a.m. - 8 p.m.
Phone: (843) 572-4094
Hurd/St. Andrews Library
Closed (Toddler Storytime)
Phone: (843) 766-2546
Baxter-Patrick James Island
9 a.m. - 8 p.m.
Phone: (843) 795-6679
Bees Ferry West Ashley Library
9 a.m. - 8 p.m.
Phone: (843) 805-6892
Village Library
9 a.m. - 1 p.m.
Phone: (843) 884-9741
Keith Summey North Charleston Library
9 a.m. – 8 p.m.
Phone: (843) 744-2489
Mobile Library
9 a.m. - 5 p.m.
Phone: (843) 805-6909
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Synthon-based ligand discovery in virtual libraries of over 11 billion compounds
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- Author(s): Sadybekov, Arman A.; Sadybekov, Anastasiia V.; Liu, Yongfeng; Iliopoulos-Tsoutsouvas, Christos; Huang, Xi-Ping; Pickett, Julie; Houser, Blake; Patel, Nilkanth; Tran, Ngan K.; Tong, Fei; Zvonok, Nikolai; Jain, Manish K.; Savych, Olena; Radchenko, Dmytro S.; Nikas, Spyros P.; Petasis, Nicos A.; Moroz, Yurii S.; Roth, Bryan L.; Makriyannis, Alexandros; Katritch, Vsevolod
- Source:
Nature; 20240101, Issue: Preprints p1-8, 8p - Source:
- Additional Information
- Abstract: Structure-based virtual ligand screening is emerging as a key paradigm for early drug discovery owing to the availability of high-resolution target structures1–4and ultra-large libraries of virtual compounds5,6. However, to keep pace with the rapid growth of virtual libraries, such as readily available for synthesis (REAL) combinatorial libraries7, new approaches to compound screening are needed8,9. Here we introduce a modular synthon-based approach—V-SYNTHES—to perform hierarchical structure-based screening of a REAL Space library of more than 11 billion compounds. V-SYNTHES first identifies the best scaffold–synthon combinations as seeds suitable for further growth, and then iteratively elaborates these seeds to select complete molecules with the best docking scores. This hierarchical combinatorial approach enables the rapid detection of the best-scoring compounds in the gigascale chemical space while performing docking of only a small fraction (<0.1%) of the library compounds. Chemical synthesis and experimental testing of novel cannabinoid antagonists predicted by V-SYNTHES demonstrated a 33% hit rate, including 14 submicromolar ligands, substantially improving over a standard virtual screening of the Enamine REAL diversity subset, which required approximately 100 times more computational resources. Synthesis of selected analogues of the best hits further improved potencies and affinities (best inhibitory constant (Ki) = 0.9 nM) and CB2/CB1selectivity (50–200-fold). V-SYNTHES was also tested on a kinase target, ROCK1, further supporting its use for lead discovery. The approach is easily scalable for the rapid growth of combinatorial libraries and potentially adaptable to any docking algorithm.
- Abstract:
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