正在加载图片...
No. 8 邓欣贤等:新型多巴胺D3受体抑制剂的发现 1781 NI* Deteced cluste Fig 1 Electrostatic potential surface of Fig 2 Positive electricity cluster of the D, receptor receptor detected by N’ prob 测并进行聚类分析.结果表明,在第3号螺旋上Asp79·残基附近探测到正电团簇(图2),在膜外第2 个LoOP的Cys150附近存在氢键供体团簇.根据以上5种探针所探测出来的位点进行聚类分析,构建 了药效团模型.如图3所示,该药效团由1个与Asp7形成静电相互作用的正电药效团元素、1个氢 键供体及2个疏水元素组成[图3(A)].药效团模型很好地与D3受体活性口袋中保守残基形成静电及 氢键相互作用[图3(B)] (A) HYD. EXT-2 ,ICysl50 EXT-I 心 HYD-2 Fig 3 D, receptor pharmacophore (A) and the interaction between the pharmacophore elements and the key residues of the D, receptor(B) (A)3 Excluded volume (EXT), 2 hydrophobic center( HYD), I positive electricity center( POS )and 1 H-bond donor( HBD )are included. The distance between POS and HBD is 0. 559 nm, POS and HYD-I is 0. 561 nm, POS and HYD-2 is 0. 638 nm: (B) the distance between H-bond donor center( HBD)and Cysl50 is 0. 196 nm, the positive electricity center and Asp79-.is 0. 351 nm. The two hydrophobic centers are lying on the lipophilic pocket of the receptor. 2.3数据库筛选 Asinex gold collection数据库包含20000°个化合物,使用 CATALYST中的 catSear模块3对其 进行筛选,筛选结果如表1所示.根据拟合度及打分函数的排序结果,结合类药性五规则,挑选出7个 化合物进行生物活性测试 Table 1 Physico-chemical parameters, G-Score and fit value of the hits Entry H-bond donor H-bond acceptor AlgP Rotatable bond G-Score Fit value 04932482 464.54 02987623 4.373 38.55 03305462 412.49 05245768 409.48 3.545 0l199 Scoring by GOLD. ) |}~*FGH *+XY
vzAu(E ) ! /
k2?u vwv |}~ + #utE D uS *+[@AdefzAu- k 2? \]Z[3E (*)4ut >?L MN¡VWXY[@A k2def3E ( )4 (!) " # ($) (*) 56#.$. 78$(59) %.%##$:$(; ) :7$$$#:#:#$:$(!). ;. .(; )$ #.$.%$.:#$$:<$$ ! . ; 8 ! . ; " 8 ! . ; " , 8<( ) :%$ .:#$$:<$$ ;. .#$:$(; ). / " 8 :%$:7$$$#:#:#$:$. *+ 8 %$:<%.%##$:$$= :%$%##>$:?:%$$#$: !" *$6. /$#: 7¢£¤ (¥¦ /** ¡ #:$#% § ¨ *FG D©¥ª:«7¬=*F *¥} ®¯ °+ (¥¦ ±¦L % & '&( 5: /8. ;. . ;. ##$: *= @::$. #$ :7$ )* + &"& & , , " , & & )*+,- & " " & + + , ),-., &"" & " , , , " & ) ).- &, & , ," " , ) ))+) & & " +" + "" + , " )..,-+ & &, , & + , + )** && , & +& , + " 11A#= 0, 1 +,