The conformation of the template was based on crystallographic ligand/receptor complex. in 3D space round the molecules where changes in the steric and electrostatic fields were predicted to enhance or lessen the activity of the compound. The CoMFA steric and electrostatic contour maps are demonstrated in Number 3. Open in a separate window Number 3 Std* coeff contour maps of CoMFA analysis with 2 ? grid spacing in combination with compound 19: (A) Steric fields: green contours indicate areas where bulky organizations increase activity; yellow contours indicate areas where bulky organizations decrease activity, and (B) Electrostatic fields: blue contours (80% contribution) represent areas where electron-donating organizations increase activity; reddish WBP4 contours (20% contribution) represent areas where electron-withdrawing organizations increase activity. The steric field is definitely characterized by green and yellow contours, in which yellow contours indicate areas where small groups would be favorable, while the green contours represent areas where small groups would decrease the activity. Compound 19 was selected as a research structure. As demonstrated in Number 3A, the N-1 position (R1) was surrounded by two small yellow contours, which suggested a minor group at this position would increase the inhibitory potency. This may explain why compounds 01, 02, 04 which possessed a minor group (e.g., Me, H) at R1 showed significantly improved activities compared to those with a heavy substituent. For instance, compounds 1C8 experienced an order for the potency of 01 > 02 > 05 > 03 > 08 > 07, with the corresponding R1 substituent Me, F3CCH2-, Cyclohexane, Phenyl, 1-piperidine-CH2-CH2-, 1-methyl-piperidine-, TBPB respectively. The presence of the yellow contour round the C-3 (R2) position also suggested a heavy group at this region would be unfavorable. By looking at up all the C-3 altered compounds, it was found that derivatives 1 and 9C14 have the activity order of 1 1 (R2 = NH2) > 10 (R2 = OH) > 11 (R2 = NHMe) > 9 (R2 = OEt) > 12 (R2 = NHcyclopropyl) > 13 (R2 = NHcyclopentyl) > 14 (R2 = NHPh). This is satisfactory in accordance with the contour map. The large yellow contour round the benzene at R3 indicated that small organizations at this position may benefit potency. This may clarify why compound 28 (R3 = SMe) was more potential than 34 (R3 = SO2NH2), while compound 34 (R3 = SO2NH2) was more active than 40 (R3 = SPh). Comparing compound 27 (R3 = Me) with 31 (R3 = compound 19. Table 4 Surflex-Dock total-score and expected activity of newly designed molecules.
198.7888.7749.17d18.9039.2938.62d29.3938.4477.20d38.3608.9499.02d48.5478.9406.53d58.9989.2867.27d68.7269.4706.57d78.6039.3478.36d88.8719.1166.68d98.8338.7317.13d108.5528.8376.50d118.7309.0277.82d128.6289.5177.51d139.0828.7135.89d149.0949.7198.45d158.7229.5077.30d168.5279.3459.25d179.1158.6755.99 Open in a separate window 3. Materials and Methods 3.1. Data Units The 47 compounds involved in this study were taken from the literature . The inhibitory activities were reported as IC50 against CDK2/cyclin A. The IC50 ideals were converted into pIC50 by taking Log TBPB (1/IC50). The entire derivatives were divided into a teaching set of 38 compounds and a test set of nine compounds for model validation. The test arranged compounds were selected randomly. Chemical constructions and connected inhibitory activities are shown in Table 5 and Table 1. Table 5 The Constructions of the Training and Test Collection Molecules.
1MeNH2HH2 Open in a separate window NH2HH3 Open in a separate window NH2HH4HNH2HH5 Open in a separate window NH2HH6i-PrNH2HH7 Open in a separate window NH2HH8 Open in a separate window NH2HH9MeOEtHH10MeOHHH11MeNHMeHH12MeNHcyclopropylHH13MeNHcyclopentylHH14MeNHPhHH15MeNH2o-CF3H16MeNH2m-CF3H17MeNH2p-CF3H18MeNH2o-AcH19MeNH2m-AcH20MeNH2p-AcH21MeNH2o-OMeH22MeNH2m-OMeH23MeNH2p-OMeH24MeNH2o-NO2H25MeNH2m-NO2H26MeNH2p-NO2H27MeNH2o-MeH28MeNH2o-SMeH29MeNH2o-NHMeH30MeNH2o-FH31MeNH2o– i-PrH32MeNH2o-CO2MeH33MeNH2o-CONH2Cl34MeNH2o-SO2NH2H35MeNH2o-PhH36MeNH2o-OPhH37MeNH2o-benzylH38MeNH2o-NHPhH39MeNH2o-benzoylH40MeNH2o-SPhH41MeNH2o-NH2H42MeNH2o-NHAcH43MeNH2o-Ac3-(4-methyl-piperazin-1-yl)44MeNH2o-Ac4-(4-methyl-piperazin-1-yl)45MeNH2o-Ac5-(4-methyl-piperazin-1-yl)46MeNH2o-OMe4-(4-methyl-piperazin-1-yl)47MeNH2o-OMe5-(4-methyl-piperazin-1-yl) Open TBPB in a separate windows 3.2. Molecular Modeling and Positioning Molecular modeling and statistical analysis were performed using the molecular.