2546 Journal of Medicinal Chemistry, 2009, VoL. 52, No 8 Paz et al B His 440 Tyr 337(Phe His 447(His 440) Phe 330 T86(Tp84) Asp 74(Asp 72) Gly 1z1(Gly 118) Ser 125 (Ser 122) Gly 118 Tyr 341 (Tyr 334) 27(he290) Tyr 12 Tyr 124 (Tyr 121) Tyr 72(Tyr 70) GIn 74 Leu 289( Leu 282 Key Ligand bond His 53 Non-ligand residues involved in hydrophobic m个 contact(s) Hydrogen bond and its length Corresponding atoms involved in hydrophobic contact(s) Figure 7. Ligplot representations of interactions of 5h with AChE.(A)Interactions in the crystal structure of the 5h/TcAChE complex.(B) Interactions in the model of the 5h/mAChE complex. In the representation of the model, mAChE numbering is followed by TcAChE numbering in brackets Table 2. Scores for the Different Conformations of the CAS and Linker Region of 5h Modeled by GOLD template for docking G_Score rank PMF rank D_Score rank chemscore rank X-SCORE rank rerank rmsd"(A) -99898-172.835 170.876 leas ee 531 218.8 107.123-17 38.27 w6c aa 14 ∠c66 5-103.5 677-43.6811 w6c ea 220 240.92 125.631 177.822 2w6c ee 447 179.1 The rmsd is calculated for each model in comparison to the crystal structure of sh. The PAS MEP moiety was omitted from the rmsd calculations of the linker, just above the MEP moiety at the CAs(Figure seems plausible that the MEP moiety adopts more than one 3). At the PAS, however, the electron density for the MEP conformation moiety is poorly defined; taken together with the fact that At the CAs, the MEP moiety is in an axial orientation and additional positive difference density is observed around it, it forms contacts with Trp84, Glyl17-119, Phe330, and His440of the linker, just above the MEP moiety at the CAS (Figure 3). At the PAS, however, the electron density for the MEP moiety is poorly defined; taken together with the fact that additional positive difference density is observed around it, it seems plausible that the MEP moiety adopts more than one conformation. At the CAS, the MEP moiety is in an axial orientation and forms contacts with Trp84, Gly117-119, Phe330, and His440 Figure 7. Ligplot representations of interactions of 5h with AChE. (A) Interactions in the crystal structure of the 5h/TcAChE complex. (B) Interactions in the model of the 5h/mAChE complex.19 In the representation of the model, mAChE numbering is followed by TcAChE numbering in brackets. Table 2. Scores for the Different Conformations of the CAS and Linker Region of 5h Modeled by GOLD template for docking G_Score rank PMF rank D_Score rank chemscore rank X-SCORE rank rerank rmsda (Å) 1ea5_aa_027 -233.44 4 -99.89 8 -172.83 5 -39.59 4 6.48 7 5.4 1.19 1ea5_ea_521 -199.81 8 -101.96 7 -170.87 6 -38.45 6 6.51 6 6.2 1.63 1ea5_ee_531 -218.8 7 -107.12 3 -176 4 -38.27 21 6.61 5 5 1.82 2w6c_aa_147 -229.92 5 -103.57 6 -169.67 7 -43.68 11 6.39 8 5.4 1.88 2w6c_ea_220 -240.92 3 -125.63 1 -177.82 2 -37.5 1 6.92 2 3.2 1.15 2w6c_ee_447 -255.25 1 -120.04 2 -179.1 1 -37.66 2 6.97 1 2.4 1.18 a The rmsd is calculated for each model in comparison to the crystal structure of 5h. The PAS MEP moiety was omitted from the rmsd calculations. 2546 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 Paz et al