創薬と結晶構造解析-3.key
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2 ? Neuraminidase and Tamiflu 2? ( )
3 Ligand-based drug design Ligand-based drug design (Pharmacophore-based drug design)?
4 Ligand-based drug design Ligand-based drug design salicylic acid O OH O O acetylsalicylic acid (Aspirin) Ibuprofen Penicillin pka COX β (?) β
5 Ligand-based drug design Ligand-based drug design Penicillin Penicillin Cefalotin Cefotaxime Cefalotin
6 Ligand-based drug design Ligand-based drug design Penicillin Penicillin amide R O NH O N S feeling HO O free carboxylate Cefalotin Cefotaxime Cefalotin Cefotaxime feeling R ( β ) LBDD ( )
7 Structure-based drug design ~1980 Structure-based drug design ~ Structure-based drug design (SBDD)
8 Structure-based drug design ~1980 SBDD LBDD ( ) SBDD 3 visual
9 LBDD & SBDD Renin SBDD 1993 Aliskiren LBDD SBDD LBDD SBDD LBDD LBDD SBDD ( ) SBDD ( ) SBDD (150mg) ? (?)
10 Renin-angiotensin system Angiotensinogen 500~600 pmol/ml Renin Angiotensin I 50~100 fmol/ml ACE Angiotensin II 30~70 fmol/ml Angiotensin II receptor Hypertension Renin 1950~1960 renin 1960~ ( ) DRVYIHPFHLVIHN... I (ACE) II II (?)
11 Renin Renin 1970 Pepstatin A IC50 20 μm 1986 CGP IC nm (MW=730) 1982 CGP IC50 7 nm (MW=1499) J Am Soc Nephrol 16: , 2005 J Am Soc Nephrol 16: , 2005 (statine)( ) IC50 50% nm 1970 A RIP( ) 1982 CGP29287 IC50 nm 1986 CGP IC50 1nM 0.7nM CGP
12 Renin Renin IC50 1nM (?) CPG % ( )
13 Renin SBDD D 3D Renin SBDD D 3D CGP CGP CGP LBDD ( ) 1980 (SBDD)
14 Renin SBDD Renin SBDD Renin + CGP Renin + CGP PDB ID: 1RNE J Struct Biol. 1991, 107(3): PDB ID: 1RNE J Struct Biol. 1991, 107(3): CGP
15 Renin SBDD Renin SBDD Renin + CGP Renin + CGP PDB ID: 1RNE J Struct Biol. 1991, 107(3): PDB ID: 1RNE J Struct Biol. 1991, 107(3): CGP38560
16 Renin SBDD Renin SBDD Renin + CGP Renin + CGP PDB ID: 1RNE J Struct Biol. 1991, 107(3): PDB ID: 1RNE J Struct Biol. 1991, 107(3): CGP38560
17 Renin SBDD 2D 3D Renin SBDD 1987 Renin + CGP CGP Chem Biol Drug Des 2007; 70: Ciba-Geigy (Novartis) SBDD ( )
18 Strategy We do not want to use peptide... Chem Biol Drug Des 2007; 70: Chem Biol Drug Des 2007; 70: ( ) CGP38560 bio-active CGP38560 CGP P1 P4 4 4 P1, P3 2 P2 P4 Ser219
19 Operational strategy tetrahydroquinoline scaffold IC nm Chem Biol Drug Des 2007; 70: Chem Biol Drug Des 2007; 70: CGP P1 P3 2 Ser219 CGP D 1 kcal/mol (?) 2 3kcal/mol IC50 0.8nM
20 THQ inhibitor CGP Ser 219 IC x x x 10-9 Chem Biol Drug Des 2007; 70: Chem Biol Drug Des 2007; 70: CGP38560 P2 P4 CGP38560 P3 P1 P3 Ser219 IC50 IC50 0.4μM 50nM Ser nM
21 Phenyl-based scaffold Phenoxy series CGP Phenyl-based inhibitor IC50 4 nm IC50 0.1μM 1 nm Chem Biol Drug Des 2007; 70: Chem Biol Drug Des 2007; 70: P3 tert-butyl IC50 0.1μM tert-butyl Ser219 3 IC50 1nM
22 SBDD SBDD 4 LBDD SBDD 4 CGP38560
23 2000 Ser Aliskiren 1993 PDB ID: 2V0Z Chem Biol. 2000, 7(7): IC50 0.6nM mg Aliskiren Ser
24 Chem Biol Drug Des 2007; 70: ( SBDD 3D SBDD 3
創薬と結晶構造解析-2.key
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