Pharmacophore Modeling for Qualitative Prediction of Antiestrogenic Activity

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Information about Pharmacophore Modeling for Qualitative Prediction of Antiestrogenic...
Health & Medicine

Published on November 2, 2009

Author: bronaldo

Source: slideshare.net

Description

A ligand-based pharmacophore approach for the prediction of antiestrogenic activity to be used as an in silico screening tool for bioactive compounds including natural products was developed using Catalyst HypoGen. The generated pharmacophore hypothesis (HYPO-7) consisted of five features, namely, one hydrophobic (HY1), two hydrophobic aromatic (HY2), one hydrogen-bond acceptor (HBA), and one hydrogen-bond donor (HBD). HYPO-7 successfully predicted the lack of cytotoxicity of a number of new metabolites isolated from the red alga Laurencia glandulifera. Furthermore, a screening of the Asinex Gold Collection database was performed by coupling HYPO-7 with a docking filtration, which resulted in a restricted set of 12 new scaffolds to be investigated as potential SERMs. The inhibitory activity of these compounds was evaluated in vitro using MCF7 human breast adenocarcinoma cell line. Ten out of the twelve compounds exhibited inhibitory activity with IC50 values between 26 and 188 μM. This result shows that application of HYPO-7 could assist in the selection of potentially active compounds, thus expediting the hit discovery process.

Supporting Information Pharmacophore modeling for qualitative prediction of antiestrogenic activity Simone Brogi,‡ Maria Kladi,† Constantinos Vagias,† Panagiota Papazafiri,§ Vassilios Roussis† and Andrea Tafi‡*Table of Contents 1. Fig. S1: superposition between the pharmacophore conformation of derivative 32 and the crystal geometry of this ligand when complexed with ER-α.---------------------------------------p 2 2. Fig. S2: superposition between the pharmacophore conformation of derivative 45 and the crystal geometry of this ligand when complexed with ER-α.---------------------------------------p 2 3. Fig. S3: best docking pose of compounds BAS-8770034, BAS0511524, BAS1813090 and raloxifene into ER-α ligand binding domain.---------------------------------------------------------p 3 4. Catalyst output file.---------------------------------------------------------------------------------------p 4 5. Aligned structures of all the studied derivatives (three-dimensional .SD file).------------------p 13 1

Figure S1 Superposition between the pharmacophore conformation of compound 32 (yellow) and thecrystal geometry of the ligand when complexed with ER-α (red).Figure S2 Superposition between the pharmacophore conformation of compound 45 (yellow) and thecrystal geometry of the ligand when complexed with ER-α (red). 2

Figure S3 Best docking pose of compounds: (a) BAS-8770034, (b) BAS0511524, (c) BAS1813090and (d) raloxifene into ER-α ligand binding domain. The side chains of residues His524, Glu353 andArg394,29 forming hydrogen bonding interactions with the ligands, are shown in tube representation.The figure suggests an interaction pattern of the derivatives retrieved from the Asinex Gold Collectiondatabase, comparable with that of raloxifene (and of the SERMs used to derive HYPO-7). 3

Output file of Catalyst runSummary of parameters: HyposReported 10 Spacing 200 MinPoints 4 MinSubsetPoints 4 SuperpositionError 1 Misses 1 FeatureMisses 1 CompleteMisses 0.0e+00 ToleranceFactor 1 CheckSuperposition 1 WeightVariation 0.3 MappingCoeff 0.0e+00 Mem 60 IdealHBondGeomOnly 0.0e+00 VariableWeight 0.0e+00 VariableTolerance 0.0e+00Constraints on numbers of features:Name: HBA HBD HYDROPHOBIC HYDROPHOB aromatiRING AROMATIC TotalMin: 0 0 0 0 0 1Max: 5 5 5 5 5 10Best records in pass 8.dumping score for hypothesis 1Definition: HBD HYDROPHOB aromatiHYDROPHOBIC RING AROMATIC 5 EVolumesWeights: 2.20191 2.20191 2.20191 2.20191Tolerances: 1.60 2.20 1.60 1.60 1.60 1.60Coords: X 0.99 0.54 1.75 3.55 -1.27 1.25 : Y -0.35 1.89 -2.30 -8.21 -8.85 -9.65 : Z 1.32 3.27 1.25 1.83 3.98 2.56 o---------> o o o--------->Excluded volume ( -4.65 , -9.14 , 1.20 ) Tol: 120.00Excluded volume ( 5.40 , -12.32 , 2.92 ) Tol: 120.00Excluded volume ( 6.00 , -6.23 , 0.62 ) Tol: 120.00Excluded volume ( 0.56 , -7.36 , -1.34 ) Tol: 120.00Excluded volume ( 4.66 , -8.15 , -3.79 ) Tol: 120.00HBD o ---> 3.0HYDROPHOB aroma2.1 4.8HYDROPHOBIC o 8.3 10.6 6.2RING AROMATIC o9.2 10.9 7.7 5.3 ---> 9.4 11.6 7.5 2.8 3.0Name Fit Cnf/Enan Mapping Est Act Error Uncarylbenzo37 7.56 93 - [50 45 54 28 ] 0.016 0.02 - 1.2 1.5diphenylfuran6dl 6.90 161 + [5 1 41 30 ] 0.074 0.039 + 1.9 1.5way3540079 6.41 7 + [18 1 26 * ] 0.23 0.079 + 2.9 1.5arylbenzo1 6.04 16 + [* 59 28 24 ] 0.55 0.3 + 1.8 1.5dnp13813 6.22 2 + [27 22 1 * ] 0.36 0.34 + 1.1 1.5tamoxifen 6.14 43 - [* 9 31 47 ] 0.43 0.48 - 1.1 1.5way-818 6.35 6 + [18 1 21 * ] 0.26 1.1 - 4.2 1.5daidzein 5.32 9 + [29 20 * 1 ] 2.8 2.3 + 1.2 1.5dnp13809 5.13 20 + [32 9 16 * ] 4.5 4.1 + 1.1 1.5compound3b 5.49 140 - [34 18 9 * ] 1.9 5 - 2.6 1.5compound6 5.17 6 + [15 18 * 1 ] 4.1 7 - 1.7 1.5compound3f 4.40 102 + [* 18 * 1 ] 24 9 + 2.6 1.5rouss2007cpd5 4.65 47 + [14 * 1 35 ] 13 11 + 1.2 1.5compound11 4.81 33 - [29 19 * 1 ] 9.2 11 - 1.2 1.5compound3g 4.40 148 + [* 28 * 1 ] 24 13 + 1.8 1.5dnp13800 4.64 21 - [12 17 * 3 ] 14 24 - 1.8 1.5bis9pmethylphenylmethyl 4.06 2 - [* * 32 17 ] 52 62 - 1.2 1.525larintero 4.17 00 + [36 11 * * ] 40 67 - 1.7 1.5lactandrato 4.06 7 + [* * 14 3 ] 52 100 - 1.9 1.517 cuparene type 3.70 25 + [16 7 * * ] 120 100 + 1.2 1.548intricenyne 4.05 8 + [35 * 10 * ] 53 120 - 2.2 1.5alfa isobromocuparene 3.67 13 + [* * 27 6 ] 130 180 - 1.4 1.5 4

24cyclolaurene 3.14 00 + [* * 22 1 ] 430 230 + 1.8 1.5alfa bromocuparene 3.10 00 + [* * 22 6 ] 470 270 + 1.8 1.5*************************************************************Mirror image used. To turn this option off, putcatHypo.forceAbsoluteStereochemistry=1 in the .Catalyst file.************************************************************* totalcost=110.774 RMS=1.53286 correl=0.974238 Cost components: Error=88.5418 Weight=1.34849 Config=20.8833 Tolerance=0Fixed Cost: totalcost=81.1791 RMS=0 correl=0 Cost components: Error=59.1709 Weight=1.12491 Config=20.8833 Tolerance=0dumping score for hypothesis 2Definition: HBD HYDROPHOB aromatiHYDROPHOBIC RING AROMATIC 3 EVolumesWeights: 2.39037 2.39037 2.39037 2.39037Tolerances: 1.60 2.20 1.60 1.60 1.60 1.60Coords: X 1.07 -1.13 1.65 3.55 -1.03 1.81 : Y -0.63 1.37 -2.43 -8.21 -8.99 -9.50 : Z 1.32 1.67 1.74 2.23 4.49 3.66 o---------> o o o--------->Excluded volume ( 2.66 , -11.97 , 1.81 ) Tol: 120.00Excluded volume ( 6.37 , -5.53 , 3.24 ) Tol: 120.00Excluded volume ( 5.95 , -9.08 , -1.34 ) Tol: 120.00HBD o ---> 3.0HYDROPHOB aroma1.9 4.7HYDROPHOBIC o 8.0 10.7 6.1RING AROMATIC o9.2 10.7 7.6 5.2 ---> 9.2 11.4 7.3 2.6 3.0Name Fit Cnf/Enan Mapping Est Act Error Uncarylbenzo37 8.56 78 + [50 49 54 28 ] 5.5e-03 0.02 - 3.6 1.5diphenylfuran6dl 7.35 6 - [5 1 41 30 ] 0.089 0.039 + 2.3 1.5way3540079 6.73 7 + [7 26 1 * ] 0.38 0.079 + 4.8 1.5arylbenzo1 6.52 53 + [* 59 31 24 ] 0.6 0.3 + 2 1.5dnp13813 6.73 9 + [4 1 * 17 ] 0.37 0.34 + 1.1 1.5tamoxifen 6.85 43 + [* 9 31 47 ] 0.28 0.48 - 1.7 1.5way-818 6.33 6 - [7 21 1 * ] 0.95 1.1 - 1.2 1.5daidzein 5.92 9 + [11 1 * 3 ] 2.4 2.3 + 1 1.5dnp13809 5.73 16 + [32 9 19 * ] 3.8 4.1 - 1.1 1.5compound3b 5.74 180 + [33 30 * 1 ] 3.7 5 - 1.4 1.5compound6 5.48 6 + [15 18 * 1 ] 6.7 7 - 1 1.5compound3f 4.78 152 + [* 18 * 1 ] 34 9 + 3.7 1.5rouss2007cpd5 5.39 47 + [14 * 1 35 ] 8.2 11 - 1.3 1.5compound11 5.59 17 - [28 19 * 1 ] 5.2 11 - 2.1 1.5compound3g 4.78 149 + [* 18 * 1 ] 33 13 + 2.6 1.5dnp13800 5.13 10 + [12 17 * 3 ] 15 24 - 1.6 1.5bis9pmethylphenylmethyl 4.60 148 - [* * 7 17 ] 51 62 - 1.2 1.525larintero 4.50 10 + [36 11 * * ] 64 67 - 1.1 1.5lactandrato 4.63 178 + [* * 58 3 ] 47 100 - 2.1 1.517 cuparene type 4.57 9 + [16 7 * * ] 54 100 - 1.9 1.548intricenyne 4.77 194 + [35 * 22 * ] 35 120 - 3.4 1.5alfa isobromocuparene 4.26 7 + [* * 27 6 ] 110 180 - 1.6 1.524cyclolaurene 3.80 5 + [* * 32 1 ] 320 230 + 1.4 1.5alfa bromocuparene 3.70 4 + [* * 35 6 ] 400 270 + 1.5 1.5*************************************************************Mirror image used. To turn this option off, putcatHypo.forceAbsoluteStereochemistry=1 in the .Catalyst file.************************************************************* totalcost=122.551 RMS=1.80081 correl=0.967272 Cost components: Error=99.7073 Weight=1.96064 Config=20.8833 Tolerance=0Fixed Cost: totalcost=81.1791 RMS=0 correl=0 Cost components: Error=59.1709 Weight=1.12491 Config=20.8833 Tolerance=0dumping score for hypothesis 3 5

Definition: HBD HYDROPHOB aromatiHYDROPHOBIC RING AROMATIC 4 EVolumesWeights: 2.25205 2.25205 2.25205 2.25205Tolerances: 1.60 2.20 1.60 1.60 1.60 1.60Coords: X 0.96 2.73 1.05 3.95 -0.84 0.92 : Y -0.97 -0.21 -2.92 -7.81 -8.51 -8.83 : Z -0.14 -2.44 1.22 3.43 3.92 6.32 o---------> o o o--------->Excluded volume ( -5.29 , -8.78 , 5.82 ) Tol: 120.00Excluded volume ( 5.95 , -10.98 , 1.79 ) Tol: 120.00Excluded volume ( -2.80 , 0.66 , 2.40 ) Tol: 120.00Excluded volume ( 0.56 , -11.98 , -2.82 ) Tol: 120.00HBD o ---> 3.0HYDROPHOB aroma2.4 4.9HYDROPHOBIC o 8.3 9.7 6.1RING AROMATIC o8.7 11.1 6.5 4.9 ---> 10.2 12.4 7.8 4.3 3.0Name Fit Cnf/Enan Mapping Est Act Error Uncarylbenzo37 8.34 8 - [50 45 54 28 ] 0.011 0.02 - 1.9 1.5diphenylfuran6dl 7.61 39 + [5 1 41 30 ] 0.057 0.039 + 1.5 1.5way3540079 7.01 14 - [18 1 31 14 ] 0.23 0.079 + 2.9 1.5arylbenzo1 6.48 33 + [* 58 1 24 ] 0.76 0.3 + 2.5 1.5dnp13813 6.51 9 - [4 1 22 * ] 0.71 0.34 + 2.1 1.5tamoxifen 6.55 34 + [* 9 44 47 ] 0.66 0.48 + 1.4 1.5way-818 6.53 2 - [7 21 1 * ] 0.69 1.1 - 1.6 1.5daidzein 6.31 10 + [29 20 * 1 ] 1.1 2.3 - 2 1.5dnp13809 5.69 4 - [32 9 19 * ] 4.8 4.1 + 1.2 1.5compound3b 6.30 39 + [34 18 3 1 ] 1.2 5 - 4.3 1.5compound6 5.42 25 - [15 18 * 1 ] 8.8 7 + 1.3 1.5compound3f 4.49 79 + [* 12 * 18 ] 75 9 + 8.4 1.5rouss2007cpd5 5.57 73 + [* 44 11 13 ] 6.3 11 - 1.7 1.5compound11 5.33 33 + [29 19 * 1 ] 11 11 - 1 1.5compound3g 4.48 145 + [* 12 * 18 ] 77 13 + 5.9 1.5dnp13800 5.60 5 - [12 15 * 3 ] 5.8 24 - 4.1 1.5bis9pmethylphenylmethyl 5.22 225 - [* 24 7 1 ] 14 62 - 4.4 1.525larintero 4.36 7 + [* * 32 1 ] 100 67 + 1.5 1.5lactandrato 4.46 231 + [* * 14 3 ] 80 100 - 1.2 1.517 cuparene type 4.33 29 + [* * 20 6 ] 110 100 + 1 1.548intricenyne 4.50 247 + [35 * 2 * ] 74 120 - 1.6 1.5alfa isobromocuparene 4.40 3 + [* * 27 6 ] 93 180 - 1.9 1.524cyclolaurene 4.37 2 + [* * 22 1 ] 100 230 - 2.3 1.5alfa bromocuparene 4.23 10 + [* * 22 6 ] 140 270 - 1.9 1.5*************************************************************Mirror image used. To turn this option off, putcatHypo.forceAbsoluteStereochemistry=1 in the .Catalyst file.************************************************************* totalcost=148.255 RMS=2.31512 correl=0.940203 Cost components: Error=126.168 Weight=1.47331 Config=20.8833 Tolerance=0Fixed Cost: totalcost=81.1791 RMS=0 correl=0 Cost components: Error=59.1709 Weight=1.12491 Config=20.8833 Tolerance=0dumping score for hypothesis 4Definition: HBD HYDROPHOB aromatiHYDROPHOBIC RING AROMATICWeights: 2.75206 2.75206 2.75206 2.75206Tolerances: 1.60 2.20 1.60 1.60 1.60 1.60Coords: X 0.21 -1.65 2.10 4.30 -1.42 -0.13 : Y -4.65 -3.61 -3.84 -0.06 -0.12 1.06 : Z -1.63 -3.74 -0.38 3.99 3.58 6.02 o---------> o o o--------->HBD o ---> 3.0HYDROPHOB aroma2.4 5.0HYDROPHOBIC o 8.3 10.4 6.2RING AROMATIC o7.1 8.1 6.5 5.7 ---> 9.6 10.9 8.4 5.0 3.0Name Fit Cnf/Enan Mapping Est Act Error Unc 6

arylbenzo37 8.85 42 - [50 49 54 28 ] 0.034 0.02 + 1.7 1.5diphenylfuran6dl 8.15 67 + [5 1 41 * ] 0.17 0.039 + 4.3 1.5way3540079 7.96 8 + [18 1 31 * ] 0.27 0.079 + 3.4 1.5arylbenzo1 7.64 6 - [* 26 59 28 ] 0.56 0.3 + 1.9 1.5dnp13813 7.72 9 - [4 1 22 * ] 0.46 0.34 + 1.4 1.5tamoxifen 8.19 34 + [* 9 31 47 ] 0.16 0.48 - 3.1 1.5way-818 7.61 2 - [18 1 21 * ] 0.59 1.1 - 1.9 1.5daidzein 7.20 10 - [11 1 20 * ] 1.5 2.3 - 1.5 1.5dnp13809 6.59 4 - [32 9 19 * ] 6.2 4.1 + 1.5 1.5compound3b 7.62 39 - [34 18 3 * ] 0.58 5 - 8.6 1.5compound6 6.70 9 + [15 18 9 * ] 4.8 7 - 1.5 1.5compound3f 5.47 73 + [* 9 * 18 ] 81 9 + 9 1.5rouss2007cpd5 6.71 73 - [* 44 11 13 ] 4.8 11 - 2.3 1.5compound11 6.36 17 + [29 19 1 * ] 10 11 - 1 1.5compound3g 5.50 230 + [* 12 * 18 ] 77 13 + 5.9 1.5dnp13800 6.52 00 + [12 17 23 * ] 7.3 24 - 3.3 1.5bis9pmethylphenylmethyl 5.50 5 + [* 18 32 * ] 76 62 + 1.2 1.525larintero 5.35 10 + [36 11 * * ] 110 67 + 1.6 1.5lactandrato 5.51 176 + [69 * 14 3 ] 75 100 - 1.3 1.517 cuparene type 5.50 4 + [* 7 34 * ] 76 100 - 1.4 1.548intricenyne 5.50 7 + [35 * 2 * ] 77 120 - 1.5 1.5alfa isobromocuparene 5.49 00 + [* 6 27 * ] 77 180 - 2.3 1.524cyclolaurene 5.22 2 + [* * 32 1 ] 150 230 - 1.6 1.5alfa bromocuparene 5.50 5 + [* 6 27 * ] 76 270 - 3.5 1.5*************************************************************Mirror image used. To turn this option off, putcatHypo.forceAbsoluteStereochemistry=1 in the .Catalyst file.************************************************************* totalcost=162.155 RMS=2.49598 correl=0.930189 Cost components: Error=137.045 Weight=4.22668 Config=20.8833 Tolerance=0Fixed Cost: totalcost=81.1791 RMS=0 correl=0 Cost components: Error=59.1709 Weight=1.12491 Config=20.8833 Tolerance=0dumping score for hypothesis 5Definition: HBA HYDROPHOB aromaHYDROPHOB aromatiHYDROPHOBIC RING AROMATIC 4EVolumesWeights: 1.98747 1.98747 1.98747 1.98747 1.98747Tolerances: 1.60 2.20 1.60 1.60 1.60 1.60 1.60Coords: X -2.98 -4.15 4.28 -0.63 5.04 1.63 1.47 : Y -0.01 0.31 4.60 0.13 -1.05 0.44 3.43 : Z 1.92 -0.82 4.76 1.81 2.69 1.35 1.47 o---------> o o o o--------->Excluded volume ( 6.32 , 1.75 , 0.64 ) Tol: 120.00Excluded volume ( 6.36 , 2.87 , -5.00 ) Tol: 120.00Excluded volume ( -8.99 , 2.70 , 4.52 ) Tol: 120.00Excluded volume ( -2.81 , -7.36 , -1.76 ) Tol: 120.00HBA o ---> 3.0HYDROPHOB aroma9.1 11.0HYDROPHOB aroma2.4 4.4 7.3HYDROPHOBIC o 8.1 9.9 6.1 5.9RING AROMATIC o4.7 6.2 6.0 2.3 4.0 ---> 5.6 6.8 4.5 3.9 5.9 3.0Name Fit Cnf/Enan Mapping Est Act Error Uncarylbenzo37 7.99 73 + [50 31 45 54 10 ] 0.014 0.02 - 1.4 1.5diphenylfuran6dl 7.12 22 - [40 2 39 41 * ] 0.11 0.039 + 2.8 1.5way3540079 6.64 7 + [7 * 26 1 13 ] 0.32 0.079 + 4.1 1.5arylbenzo1 6.98 24 + [25 46 28 59 * ] 0.15 0.3 - 2 1.5dnp13813 6.20 2 - [4 * 1 22 11 ] 0.9 0.34 + 2.6 1.5tamoxifen 6.16 13 + [20 9 34 44 * ] 0.98 0.48 + 2 1.5way-818 6.26 2 + [7 * 21 1 13 ] 0.77 1.1 - 1.4 1.5daidzein 5.26 10 + [29 1 20 * * ] 7.7 2.3 + 3.4 1.5dnp13809 5.24 4 + [32 * 9 19 * ] 8.2 4.1 + 2 1.5compound3b 5.49 29 - [34 9 28 * * ] 4.6 5 - 1.1 1.5compound6 5.53 9 - [15 9 18 * * ] 4.2 7 - 1.7 1.5compound3f 5.93 81 - [31 1 30 * * ] 1.7 9 - 5.4 1.5rouss2007cpd5 5.19 58 - [19 * 25 44 * ] 9.1 11 - 1.2 1.5 7

compound11 4.83 17 + [29 1 19 * * ] 21 11 + 1.9 1.5compound3g 5.95 152 - [29 12 28 * * ] 1.6 13 - 8.1 1.5dnp13800 5.26 00 + [12 * 17 23 * ] 7.7 24 - 3.1 1.5bis9pmethylphenylmethyl 4.55 77 - [1 * * 17 2 ] 40 62 - 1.6 1.525larintero 3.96 4 + [36 * 11 * * ] 160 67 + 2.3 1.5lactandrato 5.14 15 + [33 * 5 25 * ] 10 100 - 9.7 1.517 cuparene type 3.97 27 + [16 * 7 * * ] 150 100 + 1.5 1.548intricenyne 3.87 14 + [14 * * 35 * ] 190 120 + 1.6 1.5alfa isobromocuparene 3.91 13 + [* * * 22 6 ] 170 180 - 1 1.524cyclolaurene 3.96 2 + [* * * 22 1 ] 160 230 - 1.5 1.5alfa bromocuparene 3.91 10 + [* * * 22 6 ] 180 270 - 1.5 1.5*************************************************************Mirror image used. To turn this option off, putcatHypo.forceAbsoluteStereochemistry=1 in the .Catalyst file.************************************************************* totalcost=166.745 RMS=2.61633 correl=0.922939 Cost components: Error=144.736 Weight=1.12577 Config=20.8833 Tolerance=0Fixed Cost: totalcost=81.1791 RMS=0 correl=0 Cost components: Error=59.1709 Weight=1.12491 Config=20.8833 Tolerance=0dumping score for hypothesis 6Definition: HBD HYDROPHOB aromatiHYDROPHOBIC RING AROMATICWeights: 2.49688 2.49688 2.49688 2.49688Tolerances: 1.60 2.20 1.60 1.60 1.60 1.60Coords: X 1.93 4.41 2.10 4.30 -1.68 -1.32 : Y -6.13 -7.74 -3.84 -0.06 -3.90 -2.82 : Z -1.15 -1.65 -0.38 3.99 4.57 7.35 o---------> o o o--------->HBD o ---> 3.0HYDROPHOB aroma2.4 4.7HYDROPHOBIC o 8.3 9.5 6.2RING AROMATIC o7.1 9.5 6.2 7.1 ---> 9.7 11.8 8.5 7.1 3.0Name Fit Cnf/Enan Mapping Est Act Error Uncarylbenzo37 8.81 4 - [50 45 54 28 ] 0.011 0.02 - 1.8 1.5diphenylfuran6dl 7.47 85 - [40 39 41 * ] 0.24 0.039 + 6.2 1.5way3540079 7.25 16 - [18 1 31 * ] 0.4 0.079 + 5.1 1.5arylbenzo1 7.34 63 - [* 28 59 24 ] 0.32 0.3 + 1.1 1.5dnp13813 7.09 9 + [4 1 22 * ] 0.57 0.34 + 1.7 1.5tamoxifen 7.02 6 - [* 34 9 47 ] 0.67 0.48 + 1.4 1.5way-818 7.15 2 - [7 21 1 * ] 0.5 1.1 - 2.2 1.5daidzein 6.33 10 + [11 1 20 * ] 3.3 2.3 + 1.4 1.5dnp13809 6.07 4 + [32 9 19 * ] 6 4.1 + 1.5 1.5compound3b 6.96 188 + [34 18 12 * ] 0.78 5 - 6.4 1.5compound6 6.73 9 - [15 18 9 * ] 1.3 7 - 5.3 1.5compound3f 4.99 80 + [* * 30 1 ] 72 9 + 7.9 1.5rouss2007cpd5 6.36 9 - [14 * 11 35 ] 3.1 11 - 3.5 1.5compound11 5.81 17 + [29 19 1 * ] 11 11 - 1 1.5compound3g 4.99 152 + [* * 28 1 ] 72 13 + 5.5 1.5dnp13800 5.83 00 + [12 17 23 * ] 10 24 - 2.3 1.5bis9pmethylphenylmethyl 4.99 5 + [* 18 32 * ] 72 62 + 1.2 1.525larintero 4.97 10 + [36 11 * * ] 75 67 + 1.1 1.5lactandrato 4.99 175 + [* 8 14 * ] 72 100 - 1.4 1.517 cuparene type 4.99 4 + [* 7 34 * ] 72 100 - 1.4 1.548intricenyne 4.98 235 + [35 * 2 * ] 75 120 - 1.6 1.5alfa isobromocuparene 4.98 00 + [* 6 27 * ] 73 180 - 2.4 1.524cyclolaurene 4.60 00 + [* 9 32 * ] 180 230 - 1.3 1.5alfa bromocuparene 4.99 5 + [* 6 27 * ] 72 270 - 3.7 1.5*************************************************************Mirror image used. To turn this option off, putcatHypo.forceAbsoluteStereochemistry=1 in the .Catalyst file.************************************************************* totalcost=169.835 RMS=2.64275 correl=0.921331 Cost components: Error=146.473 Weight=2.47884 Config=20.8833 Tolerance=0Fixed Cost: 8

totalcost=81.1791 RMS=0 correl=0Cost components: Error=59.1709 Weight=1.12491 Config=20.8833 Tolerance=0dumping score for hypothesis 7Definition: HBA HBD HYDROPHOB aromaHYDROPHOB aromatiHYDROPHOBICWeights: 1.46769 1.46769 1.46769 1.46769 1.46769Tolerances: 1.60 2.20 1.60 2.20 1.60 1.60 1.60Coords: X 8.41 10.71 -2.71 -4.17 6.26 -0.21 4.79 : Y -2.78 -4.07 1.25 -0.71 -2.42 0.27 1.68 : Z -0.91 0.52 0.69 -1.04 0.97 1.02 4.48 o---------> o---------> o o oHBA o ---> 3.0HBD o 11.9 14.4 ---> 12.8 15.3 3.0HYDROPHOB aroma2.9 4.8 9.7 10.8HYDROPHOB aroma9.3 11.8 2.7 4.6 7.0HYDROPHOBIC o 7.9 9.2 8.4 10.8 5.6 6.2Name Fit Cnf/Enan Mapping Est Act Error Uncarylbenzo37 7.17 58 + [25 50 29 49 54 ] 7.2e-03 0.02 - 2.8 1.5diphenylfuran6dl 5.96 65 + [40 5 39 1 41 ] 0.13 0.039 + 3.3 1.5way3540079 5.60 14 - [7 18 14 1 31 ] 0.3 0.079 + 3.5 1.5arylbenzo1 5.13 10 - [25 * 31 59 46 ] 0.89 0.3 + 3 1.5dnp13813 5.41 12 - [4 27 1 22 * ] 0.46 0.34 + 1.3 1.5tamoxifen 5.03 34 - [20 * 31 9 44 ] 1.1 0.48 + 2.4 1.5way-818 5.45 6 + [7 18 21 1 * ] 0.42 1.1 - 2.7 1.5daidzein 4.90 9 - [11 29 1 20 * ] 1.5 2.3 - 1.5 1.5dnp13809 4.71 21 - [32 30 9 25 * ] 2.4 4.1 - 1.7 1.5compound3b 4.21 184 - [33 * 18 9 * ] 7.8 5 + 1.6 1.5compound6 4.19 10 - [15 * 18 1 * ] 8.2 7 + 1.2 1.5compound3f 4.29 120 - [31 * 30 1 * ] 6.5 9 - 1.4 1.5rouss2007cpd5 4.18 47 - [* 14 42 * 1 ] 7.2 11 - 1.5 1.5compound11 4.01 17 + [* 28 1 19 * ] 8.4 11 - 1.3 1.5compound3g 4.34 140 + [29 * 28 12 * ] 5.8 13 - 2.3 1.5dnp13800 3.81 2 + [7 * 23 * 17 ] 20 24 - 1.2 1.5bis9pmethylphenylmethyl 2.99 217 - [1 * * 20 32 ] 140 62 + 2.2 1.525larintero 2.93 7 + [* 36 * 11 * ] 160 67 + 2.3 1.5lactandrato 4.09 180 + [33 * 12 * 14 ] 10 100 - 10 1.517 cuparene type 2.94 4 + [* * * 7 34 ] 160 100 + 1.5 1.548intricenyne 2.94 2 + [* 35 * * 4 ] 160 120 + 1.3 1.5alfa isobromocuparene 2.93 15 + [* * 6 * 32 ] 160 180 - 1.1 1.524cyclolaurene 2.91 00 + [* * 9 * 32 ] 170 230 - 1.4 1.5alfa bromocuparene 2.93 5 + [* * * 6 27 ] 130 270 - 2 1.5*************************************************************Mirror image used. To turn this option off, putcatHypo.forceAbsoluteStereochemistry=1 in the .Catalyst file.************************************************************* totalcost=171.117 RMS=2.65908 correl=0.9603 Cost components: Error=147.555 Weight=2.67884 Config=20.8833 Tolerance=0Fixed Cost: totalcost=81.1791 RMS=0 correl=0 Cost components: Error=59.1709 Weight=1.12491 Config=20.8833 Tolerance=0dumping score for hypothesis 8Definition: HBA HYDROPHOB aromaHYDROPHOB aromatiHYDROPHOBIC RING AROMATIC 2EVolumesWeights: 2.12087 2.12087 2.12087 2.12087 2.12087Tolerances: 1.60 2.20 1.60 1.60 1.60 1.60 1.60Coords: X -2.43 -3.90 5.48 -1.03 4.47 4.15 3.92 : Y 0.45 -0.15 4.20 0.53 -0.97 2.25 3.65 : Z 1.42 -1.12 3.56 2.61 2.41 3.67 1.02 o---------> o o o o--------->Excluded volume ( 6.32 , 1.75 , 0.64 ) Tol: 120.00Excluded volume ( -2.81 , -7.36 , -1.76 ) Tol: 120.00HBA o ---> 3.0HYDROPHOB aroma9.0 11.4 9

HYDROPHOB aroma1.8 4.8 7.5HYDROPHOBIC o 7.1 9.1 5.4 5.7RING AROMATIC o7.2 9.7 2.4 5.6 3.5 ---> 7.1 9.0 3.0 6.1 4.9 3.0Name Fit Cnf/Enan Mapping Est Act Error Uncarylbenzo37 7.79 39 + [50 29 45 54 * ] 0.055 0.02 + 2.7 1.5diphenylfuran6dl 7.94 22 + [40 2 39 41 14 ] 0.038 0.039 - 1 1.5way3540079 7.00 8 + [18 14 1 * 13 ] 0.34 0.079 + 4.3 1.5arylbenzo1 7.59 2 - [25 46 28 47 * ] 0.086 0.3 - 3.5 1.5dnp13813 7.07 9 + [27 1 22 * 11 ] 0.29 0.34 - 1.2 1.5tamoxifen 6.62 4 - [20 * 31 44 47 ] 0.8 0.48 + 1.7 1.5way-818 5.71 6 + [18 21 1 * 13 ] 6.5 1.1 + 5.9 1.5daidzein 6.03 9 - [11 20 1 * * ] 3.1 2.3 + 1.4 1.5dnp13809 5.62 21 - [32 25 9 * * ] 8 4.1 + 2 1.5compound3b 5.80 47 - [34 * * 7 1 ] 5.4 5 + 1.1 1.5compound6 5.74 7 + [15 8 18 * * ] 6.2 7 - 1.1 1.5compound3f 6.03 28 + [31 9 18 * * ] 3.1 9 - 2.9 1.5rouss2007cpd5 5.20 32 - [18 11 * 42 * ] 21 11 + 2 1.5compound11 5.07 17 + [29 1 19 * * ] 29 11 + 2.6 1.5compound3g 6.08 57 - [29 12 18 * * ] 2.8 13 - 4.6 1.5dnp13800 5.88 21 + [12 5 17 * 2 ] 4.4 24 - 5.4 1.5bis9pmethylphenylmethyl 5.65 21 + [* * 18 7 1 ] 7.5 62 - 8.2 1.525larintero 4.58 7 + [36 * 11 32 * ] 89 67 + 1.3 1.5lactandrato 5.23 71 + [71 8 * 14 * ] 6.4 100 - 16 1.517 cuparene type 5.06 19 + [16 * 7 34 * ] 29 100 - 3.6 1.548intricenyne 4.17 9 + [14 * * 35 * ] 230 120 + 1.9 1.5alfa isobromocuparene 4.10 9 + [* * * 29 6 ] 270 180 + 1.5 1.524cyclolaurene 4.18 5 + [* * * 29 1 ] 220 230 - 1.1 1.5alfa bromocuparene 4.14 16 + [* * * 22 6 ] 240 270 - 1.1 1.5*************************************************************Mirror image used. To turn this option off, putcatHypo.forceAbsoluteStereochemistry=1 in the .Catalyst file.************************************************************* totalcost=174.475 RMS=2.7308 correl=0.915734 Cost components: Error=152.387 Weight=1.20504 Config=20.8833 Tolerance=0Fixed Cost: totalcost=81.1791 RMS=0 correl=0 Cost components: Error=59.1709 Weight=1.12491 Config=20.8833 Tolerance=0dumping score for hypothesis 9Definition: HBA HBD HYDROPHOB aromaHYDROPHOB aromatiHYDROPHOBICWeights: 1.46286 1.46286 1.46286 1.46286 1.46286Tolerances: 1.60 2.20 1.60 2.20 1.60 1.60 1.60Coords: X -3.36 -5.48 3.69 3.99 -1.26 2.98 3.34 : Y 2.40 1.44 -5.67 -6.53 1.42 -3.50 2.46 : Z 1.89 3.86 -0.50 -3.39 2.14 0.26 -0.26 o---------> o---------> o o oHBA o ---> 3.0HBD o 11.0 12.4 ---> 12.7 14.3 3.0HYDROPHOB aroma2.3 4.6 9.0 11.0HYDROPHOB aroma8.8 10.4 2.4 4.8 6.8HYDROPHOBIC o 7.0 9.8 8.1 9.5 5.3 6.0Name Fit Cnf/Enan Mapping Est Act Error Uncarylbenzo37 7.31 20 + [25 50 28 45 54 ] 4.9e-03 0.02 - 4.1 1.5diphenylfuran6dl 5.59 151 - [40 5 39 1 41 ] 0.26 0.039 + 6.6 1.5way3540079 6.15 8 - [7 18 14 1 31 ] 0.07 0.079 - 1.1 1.5arylbenzo1 5.12 68 - [25 * 31 46 59 ] 0.76 0.3 + 2.5 1.5dnp13813 5.30 9 - [4 27 1 22 * ] 0.5 0.34 + 1.5 1.5tamoxifen 5.54 15 - [20 * 28 56 44 ] 0.28 0.48 - 1.7 1.5way-818 4.46 6 + [7 18 21 1 * ] 3.4 1.1 + 3.1 1.5daidzein 4.69 9 - [11 29 1 20 * ] 2 2.3 - 1.1 1.5dnp13809 4.09 6 + [32 30 9 29 * ] 8.1 4.1 + 2 1.5compound3b 4.36 39 - [* 34 12 18 3 ] 4.3 5 - 1.2 1.5compound6 3.89 9 - [* 15 9 18 * ] 13 7 + 1.8 1.5compound3f 4.32 5 - [31 * 18 8 * ] 4.8 9 - 1.9 1.5rouss2007cpd5 3.96 47 + [* 14 42 * 1 ] 11 11 + 1 1.5 10

compound11 3.79 17 - [29 * 19 1 * ] 16 11 + 1.5 1.5compound3g 4.33 43 + [29 * 18 12 * ] 4.6 13 - 2.8 1.5dnp13800 3.97 4 - [12 3 17 * * ] 11 24 - 2.3 1.5bis9pmethylphenylmethyl 2.93 193 + [* * * 24 7 ] 120 62 + 1.9 1.525larintero 3.11 7 + [36 * 11 * 32 ] 78 67 + 1.2 1.5lactandrato 4.19 208 + [* 69 8 * 14 ] 10 100 - 10 1.517 cuparene type 3.18 9 + [16 * 7 * 31 ] 66 100 - 1.6 1.548intricenyne 2.92 235 + [* 35 * * 2 ] 120 120 - 1 1.5alfa isobromocuparene 2.93 00 + [* * 6 * 32 ] 120 180 - 1.5 1.524cyclolaurene 2.93 00 + [* * 9 * 32 ] 120 230 - 2 1.5alfa bromocuparene 2.92 16 + [* * * 6 27 ] 120 270 - 2.2 1.5*************************************************************Mirror image used. To turn this option off, putcatHypo.forceAbsoluteStereochemistry=1 in the .Catalyst file.************************************************************* totalcost=174.906 RMS=2.71624 correl=0.936679 Cost components: Error=151.396 Weight=2.70716 Config=20.8833 Tolerance=0Fixed Cost: totalcost=81.1791 RMS=0 correl=0 Cost components: Error=59.1709 Weight=1.12491 Config=20.8833 Tolerance=0dumping score for hypothesis 10Definition: HBA HYDROPHOB aromatiHYDROPHOBIC RING AROMATIC 3 EVolumesWeights: 2.00520 2.00520 2.00520 2.00520Tolerances: 1.60 2.20 1.60 1.60 1.60 1.60Coords: X 2.94 3.39 2.67 3.26 3.54 0.54 : Y 0.84 -0.26 -6.41 -2.04 -0.75 -0.84 : Z -5.86 -8.62 0.03 1.82 -3.74 -3.71 o---------> o o o--------->Excluded volume ( -6.51 , 4.98 , -2.74 ) Tol: 120.00Excluded volume ( 2.99 , -4.28 , 6.16 ) Tol: 120.00Excluded volume ( 0.67 , 1.17 , 6.08 ) Tol: 120.00HBA o ---> 3.0HYDROPHOB aroma9.4 10.6HYDROPHOBIC o 8.2 10.6 4.8RING AROMATIC o2.7 4.9 6.9 5.7 ---> 3.6 5.7 7.0 6.3 3.0Name Fit Cnf/Enan Mapping Est Act Error Uncarylbenzo37 7.77 57 + [50 31 54 10 ] 0.023 0.02 + 1.2 1.5diphenylfuran6dl 6.90 120 + [5 39 41 1 ] 0.17 0.039 + 4.5 1.5way3540079 7.13 12 - [18 14 31 1 ] 0.1 0.079 + 1.3 1.5arylbenzo1 7.05 64 + [25 46 47 28 ] 0.12 0.3 - 2.4 1.5dnp13813 5.78 2 + [4 22 * 1 ] 2.3 0.34 + 6.7 1.5tamoxifen 6.53 50 + [20 9 44 22 ] 0.41 0.48 - 1.2 1.5way-818 5.68 2 + [18 21 * 1 ] 2.9 1.1 + 2.6 1.5daidzein 5.83 10 + [11 20 * 1 ] 2 2.3 - 1.1 1.5dnp13809 5.27 21 + [32 25 * 1 ] 7.4 4.1 + 1.8 1.5compound3b 5.25 25 + [34 9 3 * ] 7.7 5 + 1.5 1.5compound6 5.71 6 - [15 12 * 18 ] 2.7 7 - 2.6 1.5compound3f 5.70 234 - [31 9 * 18 ] 2.8 9 - 3.3 1.5rouss2007cpd5 5.58 58 - [19 * 44 22 ] 3.7 11 - 2.9 1.5compound11 4.96 19 - [29 1 * 16 ] 15 11 + 1.4 1.5compound3g 5.78 212 - [29 12 * 18 ] 2.3 13 - 5.7 1.5dnp13800 4.95 26 - [12 5 * 9 ] 16 24 - 1.5 1.5bis9pmethylphenylmethyl 4.79 237 - [33 * 7 23 ] 22 62 - 2.8 1.525larintero 3.95 2 + [36 * * 1 ] 150 67 + 2.3 1.5lactandrato 5.19 9 + [71 10 14 * ] 8.8 100 - 11 1.517 cuparene type 3.99 4 + [* * 34 6 ] 140 100 + 1.4 1.548intricenyne 4.00 14 + [14 * 35 * ] 140 120 + 1.2 1.5alfa isobromocuparene 3.82 15 + [* * 32 6 ] 210 180 + 1.2 1.524cyclolaurene 3.84 00 + [* * 32 1 ] 200 230 - 1.2 1.5alfa bromocuparene 3.86 10 + [* * 27 6 ] 190 270 - 1.4 1.5*************************************************************Mirror image used. To turn this option off, putcatHypo.forceAbsoluteStereochemistry=1 in the .Catalyst file.************************************************************* totalcost=176.957 RMS=2.76807 correl=0.936307 11

Cost components: Error=154.949 Weight=1.12506 Config=20.8833 Tolerance=0Fixed Cost: totalcost=81.1791 RMS=0 correl=0 Cost components: Error=59.1709 Weight=1.12491 Config=20.8833 Tolerance=0dumping score for the null hypothesis: totalcost=636.599 RMS=6.79664 correl=0 Cost components: Error=636.599 Weight=0 Config=0 Mapping=0 Tolerance=0Version: catHypo 4.8 (189) Wednesday, June 18, 2003 at 01:02 PMConfs (cpd): /var/tmp/OutHypo-58696-154Dir/Spreadsheet: /var/tmp/OutHypo-58696-154Dir/ultimotraining26.spstDictionary: /var/tmp/OutHypo-58696-154Dir/dict.chmHost: indy.ctf.unisi.itOutname: OutHypo-58696Logname: OutHypo-58696-154.logCPU time = 11744 s System time = 8 sComplexity 110.579Concluded pass 8.Finished generating a hypothesis. 12

Aligned structures of all the studied derivatives (three-dimensional .SD file)BAS-0369551 SciTegic09220911323D 56 57 0 0 0 0 999 V2000 5.9839 -2.5007 2.7639 C 0 0 5.0889 -2.2386 1.7135 C 0 0 5.5423 -2.2134 0.3839 C 0 0 6.9006 -2.4513 0.1009 C 0 0 7.8000 -2.7142 1.1507 C 0 0 7.3419 -2.7386 2.4784 C 0 0 5.5559 -2.5245 4.0100 O 0 0 4.0441 -2.0547 1.9252 H 0 0 4.8458 -2.0111 -0.4158 H 0 0 7.3852 -2.4249 -1.3114 C 0 0 8.8428 -2.8985 0.9422 H 0 0 8.0353 -2.9411 3.2794 H 0 0 6.5501 -1.8761 -2.4372 C 0 0 8.5504 -2.8843 -1.5790 N 0 0 9.0359 -2.8670 -2.9298 O 0 0 6.5140 -2.3692 5.0474 C 0 0 7.1937 -1.0067 4.9163 C 0 0 6.3130 0.1420 5.4111 C 0 0 5.7579 0.9937 4.2698 C 0 0 4.2759 1.3261 4.4470 C 0 0 3.5152 1.3550 3.1220 C 0 0 2.1237 1.2067 3.3705 O 0 0 -0.3847 0.6694 0.1280 C 0 0 0.7237 1.5277 0.0279 C 0 0 1.5759 1.7093 1.1300 C 0 0 1.3237 1.0332 2.3364 C 0 0 0.2160 0.1735 2.4349 C 0 0 -0.6377 -0.0078 1.3345 C 0 0 -1.2902 0.4760 -1.0435 C 0 0 0.9288 2.0531 -0.8954 H 0 0 2.4255 2.3705 1.0475 H 0 0 0.0170 -0.3486 3.3597 H 0 0 -1.4880 -0.6711 1.4206 H 0 0 -0.8316 -0.2089 -2.3037 C 0 0 -2.4932 0.9108 -0.9837 N 0 0 -2.9604 1.5680 0.2019 O 0 0 7.1259 -1.3183 -3.1739 H 0 0 6.0458 -2.6914 -2.9539 H 0 0 5.7845 -1.2093 -2.0383 H 0 0 8.6300 -3.5848 -3.4356 H 0 0 7.2431 -3.1734 4.9581 H 0 0 6.0001 -2.4526 6.0045 H 0 0 7.5141 -0.8312 3.8892 H 0 0 8.1542 -1.0036 5.4306 H 0 0 6.8533 0.7618 6.1262 H 0 0 5.5043 -0.2345 6.0380 H 0 0 5.9310 0.5125 3.3081 H 0 0 6.3449 1.9047 4.1492 H 0 0 4.1551 2.2698 4.9806 H 0 0 3.8065 0.6348 5.1461 H 0 0 3.8362 0.5374 2.4755 H 0 0 3.6700 2.3033 2.6078 H 0 0 13

-1.6487 -0.2481 -3.0219 H 0 0 -0.4562 -1.2037 -2.0679 H 0 0 -0.0159 0.3567 -2.7569 H 0 0 -2.8377 0.9929 0.9699 H 0 0 1 2 2 0 1 6 1 0 1 7 1 0 2 3 1 0 2 8 1 0 3 4 2 0 3 9 1 0 4 5 1 0 4 10 1 0 5 6 2 0 5 11 1 0 6 12 1 0 7 16 1 010 13 1 010 14 2 013 37 1 013 38 1 013 39 1 014 15 1 015 40 1 016 17 1 016 41 1 016 42 1 017 18 1 017 43 1 017 44 1 018 19 1 018 45 1 018 46 1 019 20 1 019 47 1 019 48 1 020 21 1 020 49 1 020 50 1 021 22 1 021 51 1 021 52 1 022 26 1 023 24 2 023 28 1 023 29 1 024 25 1 024 30 1 025 26 2 025 31 1 026 27 1 027 28 2 027 32 1 028 33 1 029 34 1 029 35 2 034 53 1 034 54 1 0 14

34 55 1 0 35 36 1 0 36 56 1 0M END> <Name>BAS-0369551> <Absolute Energy>70.1468> <Estimate>0.671663> <FitValue>5.95936> <HBA_1>1> <HBD_2>1> <HYDROPHOBIC_5>1> <HYDROPHOB_aromatic_3>1> <HYDROPHOB_aromatic_4>1> <MappedAtoms>14036032820> <MappingID>1> <Pharmprint>11111> <Relative Energy>18.5279> <s_m_entry_id>7> <s_m_entry_name>BAS-0369551.1$$$$BAS-0511524 SciTegic09220911323D 15

50 52 0 0 0 0 999 V2000 2.0766 -0.3072 2.2176 C 0 0 1.1986 -1.2605 1.6679 C 0 0 0.0368 -0.8391 0.9959 C 0 0 -0.2523 0.5313 0.8692 C 0 0 0.6278 1.4829 1.4202 C 0 0 1.7885 1.0623 2.0926 C 0 0 3.3097 -0.7333 2.9332 C 0 0 1.4860 -2.7166 1.7903 C 0 0 -0.6361 -1.5702 0.5728 H 0 0 -1.3443 0.9149 0.2368 O 0 0 0.3362 2.9361 1.2957 C 0 0 2.4633 1.7945 2.5140 H 0 0 6.1736 -2.1778 0.0585 C 0 0 6.3072 -2.5169 1.4154 C 0 0 5.3775 -2.0503 2.3616 C 0 0 4.3053 -1.2372 1.9478 C 0 0 4.1676 -0.8975 0.5913 C 0 0 5.0989 -1.3642 -0.3531 C 0 0 7.0498 -2.6229 -0.8193 O 0 0 7.1301 -3.1412 1.7336 H 0 0 5.5380 -2.4221 3.7946 C 0 0 3.3440 -0.2726 0.2727 H 0 0 4.9422 -0.9957 -1.7849 C 0 0 4.9676 2.6226 5.0548 C 0 0 4.0380 1.7769 5.6861 C 0 0 3.4959 0.6801 4.9926 C 0 0 3.8818 0.4255 3.6657 C 0 0 4.8115 1.2714 3.0322 C 0 0 5.3519 2.3668 3.7264 C 0 0 5.4738 3.6497 5.7052 O 0 0 3.7388 1.9675 6.7045 H 0 0 2.7826 0.0349 5.4853 H 0 0 5.1116 1.0813 2.0129 H 0 0 6.0659 3.0126 3.2360 H 0 0 3.0635 -1.5250 3.6396 H 0 0 2.3793 -2.9511 2.3694 H 0 0 0.6405 -3.2152 2.2651 H 0 0 1.6116 -3.1468 0.7954 H 0 0 -1.5357 1.8569 0.1538 H 0 0 1.0819 3.5846 1.7565 H 0 0 0.2688 3.2027 0.2408 H 0 0 -0.6274 3.1550 1.7554 H 0 0 6.9532 -2.3790 -1.7488 H 0 0 4.7780 -2.0070 4.4552 H 0 0 5.5088 -3.5078 3.8937 H 0 0 6.5108 -2.0825 4.1509 H 0 0 4.0735 -0.3478 -1.8991 H 0 0 4.8757 -1.9014 -2.3888 H 0 0 5.8186 -0.4378 -2.1151 H 0 0 6.1123 4.2230 5.2586 H 0 0 1 2 2 0 1 6 1 0 1 7 1 0 2 3 1 0 2 8 1 0 3 4 2 0 16

3 9 1 0 4 5 1 0 4 10 1 0 5 6 2 0 5 11 1 0 6 12 1 0 7 16 1 0 7 27 1 0 7 35 1 0 8 36 1 0 8 37 1 0 8 38 1 0 10 39 1 0 11 40 1 0 11 41 1 0 11 42 1 0 13 14 2 0 13 18 1 0 13 19 1 0 14 15 1 0 14 20 1 0 15 16 2 0 15 21 1 0 16 17 1 0 17 18 2 0 17 22 1 0 18 23 1 0 19 43 1 0 21 44 1 0 21 45 1 0 21 46 1 0 23 47 1 0 23 48 1 0 23 49 1 0 24 25 2 0 24 29 1 0 24 30 1 0 25 26 1 0 25 31 1 0 26 27 2 0 26 32 1 0 27 28 1 0 28 29 2 0 28 33 1 0 29 34 1 0 30 50 1 0M END> <Name>BAS-0511524> <Absolute Energy>68.45> <Estimate>0.490634> <FitValue>5.61231 17

> <HBA_1>1> <HBD_2>1> <HYDROPHOBIC_5>1> <HYDROPHOB_aromatic_3>1> <HYDROPHOB_aromatic_4>1> <MappedAtoms>19010014424> <MappingID>1> <Pharmprint>11111> <Relative Energy>4.72806> <s_m_entry_id>8> <s_m_entry_name>BAS-0511524.1$$$$BAS0915895 SciTegic09220911323D 46 49 0 0 1 0 999 V2000 4.3617 1.6917 3.0192 C 0 0 4.8359 2.6541 2.1532 N 0 0 4.5061 2.6691 0.8160 C 0 0 4.9630 3.5257 0.0924 O 0 0 3.5311 0.7091 2.5992 C 0 0 3.0586 0.6558 1.1505 C 0 0 2 0 0 0 3.6596 1.7147 0.2953 N 0 0 1.5725 0.7136 1.0580 C 0 0 0.8611 -0.3512 0.4809 C 0 0 -0.5419 -0.2969 0.3955 C 0 0 -1.2364 0.8218 0.8853 C 0 0 -0.5221 1.8868 1.4629 C 0 0 0.8794 1.8326 1.5512 C 0 0 18

-2.5492 0.8725 0.8057 O 0 0 3.5295 -2.1979 2.2708 C 0 0 3.7379 -1.4883 3.4836 O 0 0 3.0641 -0.3441 3.5214 C 0 0 4.8165 -2.3875 1.5854 C 0 0 4.9642 -2.0187 0.2298 C 0 0 6.1982 -2.1943 -0.4509 C 0 0 7.2871 -2.7444 0.2325 C 0 0 7.1406 -3.1140 1.5958 C 0 0 5.9159 -2.9416 2.2732 C 0 0 8.3303 -2.8145 -0.5968 O 0 0 7.9426 -2.3041 -1.8916 C 0 0 6.5604 -1.9249 -1.7048 O 0 0 2.1230 -0.1411 4.2554 O 0 0 4.7960 1.7554 4.4643 C 0 0 5.4514 3.3639 2.5048 H 0 0 3.3673 -0.3011 0.7293 H 0 0 3.4421 1.7399 -0.6820 H 0 0 1.3872 -1.2167 0.1001 H 0 0 -1.0823 -1.1189 -0.0491 H 0 0 -1.0486 2.7504 1.8426 H 0 0 1.4212 2.6562 1.9963 H 0 0 -3.0153 1.6482 1.1472 H 0 0 2.8656 -1.6071 1.6408 H 0 0 3.1001 -3.1701 2.5126 H 0 0 4.1285 -1.5929 -0.3062 H 0 0 7.9832 -3.5376 2.1224 H 0 0 5.8260 -3.2322 3.3104 H 0 0 8.0217 -3.0798 -2.6390 H 0 0 8.5382 -1.4407 -2.1484 H 0 0 4.4259 0.8818 4.9997 H 0 0 5.8837 1.8295 4.5220 H 0 0 4.3762 2.6408 4.9380 H 0 0 1 2 1 0 1 5 2 0 1 28 1 0 2 3 1 0 2 29 1 0 3 4 2 0 3 7 1 0 5 6 1 0 5 17 1 0 6 7 1 0 6 8 1 0 6 30 1 0 7 31 1 0 8 9 2 0 8 13 1 0 9 10 1 0 9 32 1 010 11 2 010 33 1 011 12 1 011 14 1 012 13 2 012 34 1 013 35 1 014 36 1 0 19

15 16 1 0 15 18 1 0 15 37 1 0 15 38 1 0 16 17 1 0 17 27 2 0 18 19 2 0 18 23 1 0 19 20 1 0 19 39 1 0 20 21 2 0 20 26 1 0 21 22 1 0 21 24 1 0 22 23 2 0 22 40 1 0 23 41 1 0 24 25 1 0 25 26 1 0 25 42 1 0 25 43 1 0 28 44 1 0 28 45 1 0 28 46 1 0M END> <Name>BAS0915895> <Absolute Energy>111.838> <Estimate>0.07908715> <FitValue>7.03056> <HBA_1>1> <HBD_2>1> <HYDROPHOBIC_5>1> <HYDROPHOB_aromatic_3>1> <HYDROPHOB_aromatic_4>1> <MappedAtoms>24014022 20

1028> <MappingID>1> <Pharmprint>11111> <Relative Energy>31.7715> <s_m_entry_id>9> <s_m_entry_name>BAS-0915895.1$$$$BAS-1247250 SciTegic09220911323D 35 37 0 0 0 0 999 V2000 0.6405 0.9615 2.8877 C 0 0 0.6260 -0.2481 2.1681 C 0 0 -0.3404 -0.4576 1.1682 C 0 0 -1.2931 0.5349 0.8822 C 0 0 -1.2765 1.7443 1.6037 C 0 0 -0.3118 1.9585 2.6047 C 0 0 1.5818 1.1671 3.8623 N 0 0 1.3499 -1.0257 2.3710 H 0 0 -0.3486 -1.3875 0.6183 H 0 0 -2.1971 0.3383 -0.0540 O 0 0 -2.0043 2.5105 1.3896 H 0 0 -0.3167 2.8930 3.1461 H 0 0 2.9903 0.8399 3.6056 C 0 0 3.4263 -0.0514 2.6598 N 0 0 4.7939 -0.1502 2.6545 C 0 0 5.4408 0.6611 3.5935 C 0 0 4.2881 1.5336 4.4643 S 0 0 5.6780 -0.9812 1.8051 C 0 0 7.0477 -1.0852 2.1058 C 0 0 7.8870 -1.8737 1.2998 C 0 0 7.3599 -2.5623 0.1923 C 0 0 5.9897 -2.4568 -0.1061 C 0 0 5.1483 -1.6672 0.6978 C 0 0 8.1472 -3.3024 -0.5633 O 0 0 7.7130 -3.6084 -1.8800 C 0 0 1.3077 1.5422 4.7489 H 0 0 -2.8462 1.0279 -0.2395 H 0 0 6.5062 0.7418 3.7628 H 0 0 7.4619 -0.5595 2.9532 H 0 0 8.9380 -1.9504 1.5341 H 0 0 5.5786 -2.9825 -0.9548 H 0 0 4.0983 -1.5927 0.4617 H 0 0 6.6944 -3.9980 -1.8219 H 0 0 7.8560 -2.7240 -2.4996 H 0 0 8.3497 -4.3982 -2.2748 H 0 0 21

1 2 2 0 1 6 1 0 1 7 1 0 2 3 1 0 2 8 1 0 3 4 2 0 3 9 1 0 4 5 1 0 4 10 1 0 5 6 2 0 5 11 1 0 6 12 1 0 7 13 1 0 7 26 1 0 10 27 1 0 13 14 2 0 13 17 1 0 14 15 1 0 15 16 2 0 15 18 1 0 16 17 1 0 16 28 1 0 18 19 2 0 18 23 1 0 19 20 1 0 19 29 1 0 20 21 2 0 20 30 1 0 21 22 1 0 21 24 1 0 22 23 2 0 22 31 1 0 23 32 1 0 24 25 1 0 25 33 1 0 25 34 1 0 25 35 1 0M END> <Name>BAS-1247250> <Absolute Energy>62.686> <Estimate>0.506422> <FitValue>5.54368> <HBA_1>1> <HBD_2>1> <HYDROPHOBIC_5>1 22

> <HYDROPHOB_aromatic_3>1> <HYDROPHOB_aromatic_4>1> <MappedAtoms>24010022317> <MappingID>1> <Pharmprint>11111> <Relative Energy>13.0346> <s_m_entry_id>10> <s_m_entry_name>BAS-1247250.1$$$$BAS-1579754 SciTegic09220911323D 49 51 0 0 1 0 999 V2000 1.7438 2.6952 4.7901 O 0 5 1.8152 1.4782 4.6243 N 0 3 2.8119 0.9915 3.6444 C 0 0 2 0 0 0 2.2480 -0.2516 2.9196 C 0 0 2 0 0 0 3.2563 -0.8128 2.0064 N 0 0 4.5242 -1.1652 2.6644 C 0 0 2 0 0 0 5.1167 0.0649 3.3919 C 0 0 1 0 0 0 4.1255 0.6901 4.3917 C 0 0 0.9985 0.0745 2.1849 C 0 0 -0.2274 -0.4755 2.6023 C 0 0 -1.4078 -0.1657 1.9061 C 0 0 -1.3698 0.6937 0.7928 C 0 0 -0.1435 1.2425 0.3788 C 0 0 1.0390 0.9331 1.0731 C 0 0 -2.4792 0.9826 0.1411 O 0 0 5.4905 -1.7235 1.6824 C 0 0 6.0318 -3.0047 1.8783 C 0 0 6.9452 -3.5316 0.9471 C 0 0 7.3175 -2.7808 -0.1807 C 0 0 6.7713 -1.4985 -0.3751 C 0 0 5.8598 -0.9693 0.5545 C 0 0 8.1730 -3.2754 -1.0535 O 0 0 23

7.2551 0.4662 4.1777 O 0 5 6.3313 -0.3443 4.1301 N 0 3 6.3250 -1.4465 4.6311 O 0 0 4.7113 1.9895 4.9589 C 0 0 3.8653 -0.2737 5.5582 C 0 0 1.1464 0.6437 5.1888 O 0 0 2.9919 1.7844 2.9146 H 0 0 1.9927 -1.0099 3.6606 H 0 0 2.8664 -1.6594 1.5605 H 0 0 4.3261 -1.9499 3.3982 H 0 0 5.3999 0.8178 2.6560 H 0 0 -0.2644 -1.1366 3.4545 H 0 0 -2.3459 -0.5900 2.2292 H 0 0 -0.1066 1.9029 -0.4757 H 0 0 1.9786 1.3599 0.7471 H 0 0 -2.4390 1.5750 -0.6203 H 0 0 5.7528 -3.5892 2.7430 H 0 0 7.3605 -4.5165 1.1034 H 0 0 7.0548 -0.9165 -1.2400 H 0 0 5.4458 0.0166 0.3966 H 0 0 8.4209 -2.7476 -1.8238 H 0 0 5.6622 1.8221 5.4610 H 0 0 4.0261 2.4392 5.6796 H 0 0 4.8779 2.7162 4.1628 H 0 0 4.7896 -0.4946 6.0888 H 0 0 3.1453 0.1531 6.2568 H 0 0 3.4555 -1.2168 5.1941 H 0 0 1 2 1 0 2 3 1 0 2 28 2 0 3 4 1 0 3 8 1 0 3 29 1 0 4 5 1 0 4 9 1 0 4 30 1 0 5 6 1 0 5 31 1 0 6 7 1 0 6 16 1 0 6 32 1 0 7 8 1 0 7 24 1 0 7 33 1 0 8 26 1 0 8 27 1 0 9 10 2 0 9 14 1 010 11 1 010 34 1 011 12 2 011 35 1 012 13 1 012 15 1 013 14 2 013 36 1 014 37 1 015 38 1 0 24

16 17 2 0 16 21 1 0 17 18 1 0 17 39 1 0 18 19 2 0 18 40 1 0 19 20 1 0 19 22 1 0 20 21 2 0 20 41 1 0 21 42 1 0 22 43 1 0 23 24 1 0 24 25 2 0 26 44 1 0 26 45 1 0 26 46 1 0 27 47 1 0 27 48 1 0 27 49 1 0M CHG 4 1 -1 2 1 23 -1 24 1M END> <Name>BAS-1579754> <Absolute Energy>30.3974> <Estimate>0.0107041> <FitValue>6.6739> <HBA_1>1> <HBD_2>1> <HYDROPHOBIC_5>1> <HYDROPHOB_aromatic_3>1> <HYDROPHOB_aromatic_4>1> <MappedAtoms>220150171326 25

> <MappingID>1> <Pharmprint>11111> <Relative Energy>0.000411716> <s_m_entry_id>11> <s_m_entry_name>BAS-1579754.1$$$$BAS-1813090 SciTegic09220911323D 34 36 0 0 0 0 999 V2000 -0.0190 0.7276 2.7145 C 0 0 -1.1638 1.2999 2.1357 C 0 0 -1.6294 0.8478 0.8894 C 0 0 -0.9418 -0.1833 0.2219 C 0 0 0.2032 -0.7588 0.7967 C 0 0 0.6667 -0.3037 2.0457 C 0 0 0.3229 1.0888 3.6733 H 0 0 -1.6884 2.0916 2.6515 H 0 0 -2.7033 1.3854 0.3449 O 0 0 -1.2947 -0.5353 -0.7373 H 0 0 0.7168 -1.5489 0.2697 H 0 0 4.1455 -2.0474 3.8046 C 0 0 3.0281 -1.7500 4.6016 C 0 0 1.8824 -1.1761 4.0230 C 0 0 1.8540 -0.8979 2.6442 C 0 0 2.9750 -1.1953 1.8442 C 0 0 4.1228 -1.7712 2.4263 C 0 0 5.0192 -2.4890 4.2669 H 0 0 3.0485 -1.9626 5.6614 H 0 0 1.0307 -0.9548 4.6510 H 0 0 2.9545 -0.9823 0.7853 H 0 0 7.5263 -2.6759 0.0030 C 0 0 6.8277 -1.4696 -0.1837 C 0 0 5.7074 -1.1718 0.6128 C 0 0 5.2808 -2.0787 1.6015 C 0 0 5.9801 -3.2879 1.7875 C 0 0 7.0987 -3.5832 0.9906 C 0 0 8.5745 -2.9540 -0.7434 O 0 0 7.1514 -0.7689 -0.9389 H 0 0 5.1833 -0.2383 0.4559 H 0 0 5.6672 -3.9961 2.5399 H 0 0 7.6318 -4.5104 1.1371 H 0 0 -3.0115 1.0652 -0.5102 H 0 0 9.0466 -3.7857 -0.6046 H 0 0 1 2 2 0 1 6 1 0 1 7 1 0 2 3 1 0 26

2 8 1 0 3 4 2 0 3 9 1 0 4 5 1 0 4 10 1 0 5 6 2 0 5 11 1 0 6 15 1 0 9 33 1 0 12 13 2 0 12 17 1 0 12 18 1 0 13 14 1 0 13 19 1 0 14 15 2 0 14 20 1 0 15 16 1 0 16 17 2 0 16 21 1 0 17 25 1 0 22 23 2 0 22 27 1 0 22 28 1 0 23 24 1 0 23 29 1 0 24 25 2 0 24 30 1 0 25 26 1 0 26 27 2 0 26 31 1 0 27 32 1 0 28 34 1 0M END> <Name>BAS-1813090> <Absolute Energy>51.1212> <Estimate>1.023377> <FitValue>5.52029> <HBA_1>1> <HBD_2>1> <HYDROPHOBIC_5>0> <HYDROPHOB_aromatic_3>1> <HYDROPHOB_aromatic_4> 27

1> <MappedAtoms>280902550> <MappingID>1> <Pharmprint>11110> <Relative Energy>0.213574> <s_m_entry_id>12> <s_m_entry_name>BAS-1813090.1$$$$BAS-1832998 SciTegic09220911323D 47 49 0 0 0 0 999 V2000 4.1933 1.4786 4.1972 C 0 0 3.2302 0.7680 3.2791 C 0 0 3.5707 -0.4470 2.7944 C 0 0 2.6470 -1.1711 1.8915 C 0 0 2.9995 -2.2554 1.4869 O 0 0 3.6276 2.6825 4.5337 F 0 0 4.4093 0.7428 5.3310 F 0 0 5.3888 1.6984 3.5603 F 0 0 2.0570 1.3581 2.9685 O 0 0 1.1321 0.8030 2.1541 C 0 0 1.3698 -0.4728 1.5791 C 0 0 0.4097 -1.0648 0.7254 C 0 0 -0.7962 -0.3786 0.4462 C 0 0 -1.0411 0.8937 1.0180 C 0 0 -0.0772 1.4849 1.8730 C 0 0 -1.1882 4.0098 4.3454 C 0 0 -1.0067 2.6974 3.7496 N 0 0 -0.3309 2.8085 2.4674 C 0 0 -0.2577 1.8321 4.6450 C 0 0 -2.1868 1.5314 0.7445 O 0 0 4.7374 -1.0036 3.1225 O 0 0 5.5243 -1.4518 2.1659 C 0 0 6.2423 -2.6482 2.3417 C 0 0 7.0810 -3.1262 1.3208 C 0 0 7.2058 -2.4103 0.1144 C 0 0 6.4887 -1.2138 -0.0611 C 0 0 5.6500 -0.7358 0.9598 C 0 0 28

7.5542 -2.7203 -2.1853 C 0 0 7.9935 -2.8575 -0.8416 O 0 0 0.5852 -2.0361 0.2831 H 0 0 -1.5303 -0.8283 -0.2050 H 0 0 -1.7426 4.7121 3.7223 H 0 0 -1.7189 3.9104 5.2909 H 0 0 -0.2122 4.4501 4.5563 H 0 0 0.6126 3.3357 2.5980 H 0 0 -0.9419 3.4033 1.7871 H 0 0 -

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