In silico prediction and experimental evaluation of furanoheliangolide sesquiterpene. lactones as potent agents against Trypanosoma brucei rhodesiense

Transcription

1 1 Appendix 2 Supplemental material In silico prediction and experimental evaluation of furanoheliangolide sesquiterpene lactones as potent agents against Trypanosoma brucei rhodesiense 6 7 Thomas J. Schmidt a, Fernando B. Da Costa b, Norberto P. Lopes b, Marcel Kaiser c,d and Reto Brun c,d a Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, Corrensstr. 48, D Münster, Germany. b School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Av. do Café s/no., Ribeirão Preto, SP, Brazil. c Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, CH-4002 Basel, Switzerland d University of Basel *Address correspondence to Thomas J. Schmidt, thomschm@uni-muenster.de 18

2 Table A1. In vitro activity data of STL 1 73 against T. brucei rhodesiense used in the current QSAR analysis (IC 50 (µm), pic 50 = log IC 50 (M)). Each entry represents the mean of two independent measurements. pic 50 (calc.) values calculated with QSAR equation 1 are reported for the training (A) and test set (B) as well as for compounds predicted to have high activity (C) and tested after the predictions. Compound IC 50 (µm) pic 50 pic 50 (calc.) Train/Test/Pred. Data from A Ref. (7) B Ref. (7) B Ref. (7) A Ref. (7) A Ref. (7) A Ref. (7) B Ref. (7) B Ref. (7) A Ref. (7) B Ref. (7) A Ref. (7) A Ref. (7) A Ref. (7) B Ref. (7) A Ref. (7) B Ref. (7) B Ref. (7) A Ref. (7) A Ref. (7) A Ref. (7) A Ref. (7) A Ref. (7) A Ref. (7) A Ref. (7) B Ref. (7) A Ref. (7) B Ref. (7) A Ref. (7) A Ref. (7) B Ref. (7) A Ref. (7) B Ref. (7) A Ref. (7) B Ref. (7)

3 A Ref. (7) A Ref. (7) B Ref. (7) A Ref. (7) A Ref. (7) A Ref. (7) A this study A this study B this study A this study A this study A Ref (10) A Ref (10) B Ref (9) A this study A Ref (15) A Ref (15) A this study A Ref (9) A Ref (9) A this study B Ref (9) B this study B Ref (8) B Ref (8) A Ref (8) B Ref (8) A this study A this study A Ref (15) B this study B Ref (11) A Ref (11) A Ref (11) A Ref (11) C this study C this study C this study C this study

4 Table A2. Molecular descriptors taken into consideration during GA-MLR QSAR modeling. The last column (%) reports the relative occurrence of each descriptor in the final optimized population of QSAR equations (100 equations). CODE CLASS DESCRIPTION rel. occurrence (%) AM1_dipole i3d Dipole moment AM1_HOMO i3d HOMO energy (ev) AM1_HOMO_1 i3d HOMO-1 energy (ev) AM1_HOMO_2 i3d HOMO-2 energy (ev) AM1_HOMO_3 i3d HOMO-3 energy (ev) AM1_LUMO i3d LUMO energy (ev) 2 AM1_LUMO_1 i3d LUMO+1 energy (ev) AM1_LUMO_2 i3d LUMO+2 energy (ev) 9 AM1_LUMO_3 i3d LUMO+3 energy (ev) ASA i3d Water accessible surface area 4 ASA+ i3d Positive accessible surface area 6 ASA- i3d Negative accessible surface area 1 ASAN1 i3d Fract. neg accessible surface area 1 ASAN2 i3d Fract. neg accessible surface area 2 ASAN3 i3d Fract. neg accessible surface area 3 ASAN4 i3d Fract. neg accessible surface area 4 ASAN5 i3d Fract. neg accessible surface area 5 ASAN6 i3d Fract. neg accessible surface area 6 ASAN7 i3d Fract. neg accessible surface area 7 2 ASAP1 i3d Fract. pos accessible surface area 1 1 ASAP2 i3d Fract. pos accessible surface area 2 ASAP3 i3d Fract. pos accessible surface area 3 ASAP4 i3d Fract. pos accessible surface area ASAP5 i3d Fract. pos accessible surface area 5 1 ASAP6 i3d Fract. pos accessible surface area 6 ASAP7 i3d Fract. pos accessible surface area 7 1 ASA_H i3d Total hydrophobic surface area ASA_P i3d Total polar surface area CASA+ i3d Charge-weighted positive surface area 3 CASA- i3d Charge-weighted negative surface area 4 DASA i3d Absolute difference in surface area 26 DCASA i3d Absolute difference in charge-weighted areas dens i3d Mass density (AMU/A^3) dipole i3d Dipole moment ENONCS 2D ASA of enon beta carbon 100 ENONS 2D ASA of enon groups 2 FASA+ i3d Fractional positive accessible surface area 27

5 Fractional negative accessible surface 36 FASA- i3d area FASA_H i3d Fractional hydrophobic surface area FASA_P i3d Fractional polar surface area FCASA+ i3d Fractional charge-weighted positive surface area Fractional charge-weighted negative FCASA- i3d surface area glob i3d Molecular globularity 6 logp(o/w) 2D Log octanol/water partition coefficient npr1 i3d Normalized PMI ratio (1) (pmi1 / pmi3) 5 npr2 i3d Normalized PMI ratio (2) (pmi2 / pmi3) rgyr i3d Radius of gyration 2 std_dim1 i3d Standard dimension 1 2 std_dim2 i3d Standard dimension 2 std_dim3 i3d Standard dimension 3 vol i3d Van der Waals volume 1 VSA i3d Van der Waals surface area 2 vsurf_a i3d Amphiphilic moment vsurf_cp i3d Critical packing parameter 1 vsurf_cw1 i3d Capacity factor at vsurf_cw2 i3d Capacity factor at vsurf_cw3 i3d Capacity factor at vsurf_cw4 i3d Capacity factor at -2.0 vsurf_cw5 i3d Capacity factor at vsurf_cw6 i3d Capacity factor at -4.0 vsurf_cw7 i3d Capacity factor at -5.0 vsurf_cw8 i3d Capacity factor at -6.0 vsurf_d1 i3d Hydrophobic volume at vsurf_d2 i3d Hydrophobic volume at vsurf_d3 i3d Hydrophobic volume at vsurf_d4 i3d Hydrophobic volume at vsurf_d5 i3d Hydrophobic volume at vsurf_d6 i3d Hydrophobic volume at vsurf_d7 i3d Hydrophobic volume at vsurf_d8 i3d Hydrophobic volume at vsurf_dd12 i3d vsurf_edmin1, vsurf_edmin2 distance vsurf_dd13 i3d vsurf_edmin1, vsurf_edmin3 distance vsurf_dd23 i3d vsurf_edmin2, vsurf_edmin3 distance vsurf_dw12 i3d vsurf_ewmin1, vsurf_ewmin2 distance vsurf_dw13 i3d vsurf_ewmin1, vsurf_ewmin3 distance vsurf_dw23 i3d vsurf_ewmin2, vsurf_ewmin3 distance vsurf_edmin1 i3d Lowest hydrophobic energy 2 vsurf_edmin2 i3d 2nd lowest hydrophobic energy 2 vsurf_edmin3 i3d 3rd lowest hydrophobic energy 4

6 vsurf_ewmin1 i3d Lowest hydrophilic energy vsurf_ewmin2 i3d 2nd lowest hydrophilic energy vsurf_ewmin3 i3d 3rd lowest hydrophilic energy vsurf_g i3d Surface globularity vsurf_hb1 i3d H-bond donor capacity at -0.2 vsurf_hb2 i3d H-bond donor capacity at -0.5 vsurf_hb3 i3d H-bond donor capacity at -1.0 vsurf_hb4 i3d H-bond donor capacity at vsurf_hb5 i3d H-bond donor capacity at -3.0 vsurf_hb6 i3d H-bond donor capacity at -4.0 vsurf_hb7 i3d H-bond donor capacity at -5.0 vsurf_hb8 i3d H-bond donor capacity at -6.0 vsurf_hl1 i3d First hydrophilic-lipophilic balance 1 vsurf_hl2 i3d Second hydrophilic-lipophilic balance vsurf_id1 i3d Hydrophobic integy moment at -0.2 vsurf_id2 i3d Hydrophobic integy moment at -0.4 vsurf_id3 i3d Hydrophobic integy moment at -0.6 vsurf_id4 i3d Hydrophobic integy moment at -0.8 vsurf_id5 i3d Hydrophobic integy moment at -1.0 vsurf_id6 i3d Hydrophobic integy moment at -1.2 vsurf_id7 i3d Hydrophobic integy moment at vsurf_id8 i3d Hydrophobic integy moment at vsurf_iw1 i3d Hydrophilic integy moment at -0.2 vsurf_iw2 i3d Hydrophilic integy moment at -0.5 vsurf_iw3 i3d Hydrophilic integy moment at -1.0 vsurf_iw4 i3d Hydrophilic integy moment at -2.0 vsurf_iw5 i3d Hydrophilic integy moment at -3.0 vsurf_iw6 i3d Hydrophilic integy moment at -4.0 vsurf_iw7 i3d Hydrophilic integy moment at -5.0 vsurf_iw8 i3d Hydrophilic integy moment at -6.0 vsurf_r i3d Surface rugosity vsurf_s i3d Interaction field area 4 vsurf_v i3d Interaction field volume vsurf_w1 i3d Hydrophilic volume at -0.2 vsurf_w2 i3d Hydrophilic volume at -0.5 vsurf_w3 i3d Hydrophilic volume at -1.0 vsurf_w4 i3d Hydrophilic volume at -2.0 vsurf_w5 i3d Hydrophilic volume at -3.0 vsurf_w6 i3d Hydrophilic volume at -4.0 vsurf_w7 i3d Hydrophilic volume at -5.0 vsurf_w8 i3d Hydrophilic volume at -6.0 vsurf_wp1 i3d Polar volume at vsurf_wp2 i3d Polar volume at vsurf_wp3 i3d Polar volume at -1.0 vsurf_wp4 i3d Polar volume at

7 vsurf_wp5 i3d Polar volume at -3.0 vsurf_wp6 i3d Polar volume at -4.0 vsurf_wp7 i3d Polar volume at -5.0 vsurf_wp8 i3d Polar volume at -6.0 Weight 2D Molecular weight (CRC) 1 Table A3. Correlation matrix of the Y (pic 50 ) and X variables in the final QSAR equation 1. pic50_tbr ENONCS ASAP4 FASA vsurf_d6 vsurf_d8 pic50_tbr 1 ENONCS ASAP FASA vsurf_d vsurf_d Table A4. Statistical parameters of the MLR model for the training set represented by equation 1. Summary of MLR Regression Y and X variables standardized (1/StDev) Regression statistics Multiple correlation coefficient Coefficient of determination Adjusted coeff. of determinatio Standard error # of observations 46 ANOVA Degrees of freedom (d Squared sums (SS) Mean square sum (MS) F value F krit Regression E 11 Residue Total Coefficients Standard error t statistics P value Lower 95% Upper 95% intercept ENONCS E ASAP FASA E vsurf_d E vsurf_d E

8 number of compounds Training set Test set pic50 (Tbr) Fig. A1. Activity histogram for the training and test sets. The activity range for each set was evenly divided into 5 intervals and the number of compounds in each interval is plotted vs. activity.