19 12 2007 12 PROGRESS IN CHEMISTRY Vol. 19 No. 12 Dec., 2007 3 ( 210009),,, : Q503 ; O643132 : A : 10052281X(2007) 1221947208 Biocatalysis in Drug Discovery and Development Chen Yijun 3 Wu Xuri (Laboratory of Chemical Biology, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China) Abstract Due to the advantages including mild conditions, high catalytic efficiency, high stereoselectivity and regioselectivity and less byproducts, biocatalysis has been widely utilized and applied in drug discovery and development. Moreover, biocatalysts can be structurally changed and optimized through new technologies such as directed evolution, which could be better suited for biocatalytic processes. In this review, recent progress in the field of application of biocatalysis in drug discovery and development is briefly introduced and discussed. Key words biocatalysis ; biocatalyst ; metabolites ; chiral drugs ; drug discovery and development [2 ] 70,, ( 44 %) [1 ], (30 %), [3, ],,,, ph 1 [4 ],,,, 112 111,, : 2007 8 3 e2mail :yjchen - cpu @yahoo. com. cn,
1948 19, 211,,,,Michels [6 ] : (1) ; (2), ; (3) ; (4), [5 ],, 2, 96, 16 25, (bergenin 1), 3 (1) : [6 ] 1 bergenin Fig. 1 Process of generating bergenin derivatives by combinatorial biocatalysis [6 ]
12 1949 ( ) ( ) ( [7 ] ) ( ) ( ),,,de la Ggutte [8 ], 2 Loratadine hydroxyzine, Fig. 2 Biotransformation and active metabolites of loratadine and hydroxyzine 212 [10 ], P450 P450,,,,, (14), ( S)262 (11), 62 [9 ] : (1) (10) ; (2) ; (3) 11 13, Streptomyces ; (4) ; (5) antibioticus (14) ( S )262 ; (6) (11) [16 ] (3) : ( desloratadine 7) (loratadine 6) ( 2), 10 [10 ],, (cetirizine 9) (hydroxyzine 8) (2), H1 [11 ],, [16 ] [12 15 ] 3 62Hydroxybuspirone buspirone Fig. 3 Biotransformation of 62hydroxybuspirone and 213 buspirone [16 ], [10 ]
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12 1951,, 9815 % NADH, ( S)262 (32) Ceranopril 62, (30) D2 22 262 2L2 (29) Hanson [21 ] Providencia alcalifaciens N2 2 2L2 (31) ( S)262 (32), 31 32 (6), ee [22 (27) 28, 28 98 %, R ] L2 2L2 NADH ( 29) ( 6), 95 %, ee [21,22 ] 6 [21,22 ] Fig. 6 Reactions catalyzed by oxidoreductases 31212, ( S )2tertiary leucine ( 37) Thermoactinomyces intermedius, 36 37 (8), 35 95 %, ee 9915 % NADH Patel [23 ] Sphingomonas paucimobilis L2 2 34 (LAT) allysine ethylene acetal (39) 35 (7), LAT E. coli 3, 8 2, ( S )2allysine ethylene acetal [25, ( GOX) ] Hanson [26 ], 65 % 67 % 31213 39 (8) NADH H +, CO 2 H + HIV21, [24 ] ( S )2 Thermoactinomyces intermedius 38,,
1952 19 [23 ] 7 Fig. 7 Reactions catalyzed by aminotransferases [23 ] [24,26 ] 8 [24,26 ] Fig. 8 Reductive aminations in biocatalysis [30,31 ], 4 [32 ],,,,,,, ph, ( R)2 Terao [33 ], 74 (68277), 188, 411, 412, [27 ] Declerck [28 ] (), Pichia stipitis ( PsXDH) Annaluru [29 ] PsXDH,, 1018, 2018,,,,
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