5 Virtual screening in drug discovery 1
( ) Hits 2
= = docking-based) = ligand similarity-based = pharmacophore-based) 3
4
2D 3D 5
Chemoinformatics chemical informatics Cheminformatics chemi-informatics Procedia Engineering, 2012, 1264 1275 6
ADME/T - 7
2D 3D 1D CH 3 CHO 2D H 3 C C O H 3D 8
2D SMILES Simplified Molecular Input Line Entry System SLN Sybyl linear notation Sybyl 9
SMILES = # CH 4 C C 2 H 5 OH CCO HCN C#N C 6 H 12 C1CCCCC1 C 5 H 5 N n1ccccc1 10
/ \ [ ] @ @@ (CH 3 ) 2 CHCO 2 H CC(C)C(=O)O Br/C=C/Br Br\C=C\Br Br\C=C/Br Br/C=C\Br L- N[C@@H](C)C(=O)O D- N[C@H](C)C(=O)O 11
H H C C C N C O C C C O C C H 12
13
1 Cartesian coordinates x, y, z 14
2 3 1,2- r1 r2 α 15
16
MDL MOL MACSS Tripos MOL2 CSD FDAT CIF PDB PDB ENT 17
18
19
ISIS (Integrated Scientific Information Management System) MDL (1) ISIS/DRAW (2) ISIS/BASE (3) ISIS/HOST 20
2D 21
2D 3D CH 3 O H N O CH 3 N H 22 3D 3D 23
chemical diversity chemical similarity 23
combinatorial chemistry libraries combinatorial compound libraries combinatorial library 24
25
FCD (Fine Chemicals Directory) MDL 90 000 20 000 CAS ACD (Available Chemicals Directory) MDL FCD 25 CSD Cambridge Structure Database) 20 3D 26
27
(bioinformatics) 28
RNA DNA 29
PowerEdge 6400 30
sequence analysis ( ) 20 Ala A 1.8 Gly G -0.4 Pro P -1.6 Arg R -4.5 His H -3.2 Ser S -0.8 Asn N -3.5 Ile I 4.5 Thr T -0.7 Asp D -3.5 Leu L 3.8 Trp W -0.9 Cys C 2.5 Lys K -3.9 Tyr Y -1.3 Gln Q -3.5 Met M 1.9 Val V 4.2 Glu E -3.5 Phe F 2.8 31
Glu α- Val β- Pro α- β- (α) (β) Glu 1.59 0.52 Val 0.90 1.87 Pro 0.34 0.31 Ala 1.41 0.72 Leu 1.34 1.22 Lys 1.23 0.69 =1 1 1 32
( ) sequence alignment 33
( ) multiple sequence alignment 34
FKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELRE ATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQ LITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKG MNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKL LGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVW SYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPP ICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARD 35
ab initio threading homology modeling theory-based prediction knowledge-based prediction 36
1 ab initio prediction 37
2 homologous model building comparative molecular modeling homology modeling protein homology 30% 38
1 2 3 4 2 1 3 4 39
3 threading fold recognition E1 E2 threading 40
GenBank NIH NCBI Nucleic Acid Database NDB European Molecular Biology Laboratory EMBL European Bioinformatics Institute, EBI DNA Data Bank of Japan DDBJ Center for Information Biology, CIB 41
PDB Protein Data Bank at Brookhaven National Laboratories Research Collaboration for Structural Bioinformatics, RCSB 42
43
virtual screening (computer-aided screening) screening in silico 44
45
target-based virtual screening docking 46
1B PTP1B 1,700 48
48
49
50
1 1) X- R NMR RMSD 3D 2) 51
3) site-mutation Insite II / Bind site analysis Sybyl / Site ID 52
2 2D 3D 53
3 3 / ~ / /20 54
4 ( consensus score) 55
56
[ ], human immunodeficiency virus, HIV 57
HIV-PR, HIV-PR HIV-PR 58
1. X- 2. DOCK DOCK CSD, > 200 :, R OH N O F R = Br : R=Cl: 3. :, ( K i = 0.1 nm) 59
SARS-CoV 3CL Severe Acute Respiratory Syndrome SARS SARS SARS-Cov 60
SARS-Cov E small envelope protein S spike glycoprotein M membrane protein N nucleocapsid protein polymerase 3C 3C like proteinase, 3CL 61
3CL SARS : 62
1. (1) 3CL (GenBank) PDB BLAST (2) TGEV M PRo 3CL (3) TGEV M PRo X- 3CL Sybyl 6.8 / SiteID 63
1 TGEV M PRo 2 3CL TGEV M PRo 3CL M PRo 3CL 64
2. - (Sybyl 6.8 / MOLCAD ) C A. TGEV M PRo B. SARS 3CL C. 3CL TGEV M PRo SARS 65
3. SARS 3CL TGEV M PRo SGI Origin 3800 392CPU 1 ACD MDDR SPECS CNPD 1 DOCK 4.0 1000 2 Cscore AutoDock 3.0 100 300 SARS 66
4. 1 3CL 7 2 P3 SARS 5-HT Cinanserin SARS 3 CADD 67
[ ] AChE Alzheimer s Disease AD ACh AChE β- Aβ AD acetylcholinesterase AChE Aβ AChE Meptazinol Aβ AChE PAS Xie Q et al. J. Med. Chem. 2008,51(7):2027 68
PAS N (CH 2 ) n N OH HO n=2-12 n=9 AChE IC 50 3.9 nm 2 AChE Aβ IC 50 =79 µm 69
mache PDB mache PDB 2HA2 n=9 CORINA N Tripos GOLD 3.0 SYBYL / CScore X- SCORE 70
AChE PAS 71
Trp86 His447 Tyr124 PAS Trp286 n=9 mache Ligplot 72
73
His440 Trp84 Trp279 Tyr70 Glu73 n=9 TcAChE Ligplot 74
ligand similarity-based virtual screening ( ) 75
1 76
1 O query O N O N O O N N O N O N N N N O N O N N N N O O O O N 77
2 78
1) 2) 2D- 79
2 80
[ ] 81
HIV-1 HIV-1 Raltegravir 4 Bioorg. Med. Chem. Lett., 21, 6724-6727, 2011 82
15 2D- 2D/3D Visualizer in CATALYST 3D- CHARMm in CATALYST CatConf in CATALYST HipHop in CATALYST pharmacophore hypothesis 83
4 1 (HRA), 3 (HBA) 6 84
4 CATALYST pharmacophore fit values 2.23 ~ 2.98 89 8 3 IC 50 = 77 89 μm HIV 1 EC 50 = 0.317 μm 85
86
21 21 AutoDock 87
inverse screening 88
target identification multitarget approach natural product profiling selectivity profiling drug repositioning safety profiling metabolism profiling 89
1 TarFisDock (Target Fishing Docking) DDDC TarFisDock PDTD http://www.dddc.ac.cn/tarfisdock 90
PDTD (potential drug target database) TarFisDock PDTD 91
4H-Tamoxifen Tamoxifen 4H-Tamoxifen 10 TarFisDock 4H-Tamoxifen TarFisDock PDTD Nucleic Acids Research, 2006, 34, W219 2% 4H-Tamoxifen Rank 4, 10, 12) 5% Rank 21 27) 4H-Tamoxifen 30% 50% 2% 5% TarFisDock PDTD 92
2 PharmTargetDB PharmMapper PharmTargetDB 7302 6 hydrophobic center (H), positivecharged center (P), negative-charged center (N), hydrogen bond acceptor vector (HBA), hydrogen bond donor vector (HBD) and aromatic plane (AR) 1 metal interaction center (M) PharmMapper Nucleic Acids Research, 2010, 38, W609 93
PharmMapper : http://59.78.96.61/pharmmapper 94
tamoxifen PharmMapper 912 hits 11 100 4 95
A OH 14 2 1 10 9 8 3 4 5 6 7 11 13 15 OH 12 A : C 2 C 12 Molecules, 2016, 12: 1303 96
A PharmMapper PharmTargetDB 7302 118 46 (39%) IGF1R, INSR, MDM2, PARG, RXRA, PTN1, RXRB RARG A >3.5 97
ClueGo A PharmGKB, KEGG, CTD TTD insulin receptor substrate binding insulin receptor binding protein tyrosine kinase activity retinoid X receptor binding steroid hormone receptor activity 5 98
ClueGo A signaling pathway PI3K-Akt pathways in cancer proteoglycans in cancer FOXO prolactin AMPK PPAR insulin thyroid hormone 99
A insulin receptor substrate binding insulin receptor binding protein tyrosine kinase activity thyroid hormone receptor subtype-β A AKT signaling pathway 100
p-ir insulin receptor substrate 1 IRS-1 AKT S473 T308 A (Y018) HepG2 A IRS-1 AKT 101