The active site of 3CL proteinase (3CLpro) for coronavirus was identified by comparing the crystal structures of human and porcine coronavirus. The inhibitor of the main protein of rhinovirus (Ag7088) could bind with...The active site of 3CL proteinase (3CLpro) for coronavirus was identified by comparing the crystal structures of human and porcine coronavirus. The inhibitor of the main protein of rhinovirus (Ag7088) could bind with 3CLpro of human coronavirus, then it was selected as the reference for molecular docking and database screening. The ligands from two databases were used to search potential lead structures with molecular docking. Several structures from natural products and ACD-SC databases were found to have lower binding free energy with 3CLpro than that of Ag7088. These structures have similar hydrophobicity to Ag7088. They have complementary electrostatic potential and hydrogen bond acceptor and donor with 3CLpro, showing that the strategy of anti-SARS drug design based on molecular docking and database screening is feasible.展开更多
For Histone Deacetylase (HDAC) Inhibitor, four 3D-QSAR models for four types of different activities,were constructed. The cross-validated q 2 value of CoMFA Model 1 is 0.624 and the noncross-validated r 2 value is ...For Histone Deacetylase (HDAC) Inhibitor, four 3D-QSAR models for four types of different activities,were constructed. The cross-validated q 2 value of CoMFA Model 1 is 0.624 and the noncross-validated r 2 value is 0.939. The cross-validated q 2 value of Model 2 for training set is 0.652 and the noncross-validated r 2 value is 0.963. The cross-validated q 2 value for Model 3 is 0.713,with noncross-validated r 2 value 0.947. The cross-validated q 2 value for Model 4 is 0.566 with noncross-validated r 2 value 0.959. Their predicted abilities were validated by different test sets which did not include in training set. Then the relationship between substituents and activities was analyzed by using these models and the main influence elements in different positions (positions 8 and 14) were found. The polar donor electron group of position 8 could increase the activity of inhibition of HDAC,because it could form chelation with the catalytic Zn. Suitable bulk and positive groups at position 14 are favorable to anti-HDAC activity. These models could well interpret the relationship between inhibition activity and apicidin structure affording us important information for structure-based drug design.展开更多
基金Project supported by the Minister of Science and Technology of China (Nos. 2003CB114401 and 2002AA231011) the National Natural ScienceFoundation of China (No. 20073058)+1 种基金 Science and Technology Committee of Shanghai (No. 02DJ14013) Chinese Academy
文摘The active site of 3CL proteinase (3CLpro) for coronavirus was identified by comparing the crystal structures of human and porcine coronavirus. The inhibitor of the main protein of rhinovirus (Ag7088) could bind with 3CLpro of human coronavirus, then it was selected as the reference for molecular docking and database screening. The ligands from two databases were used to search potential lead structures with molecular docking. Several structures from natural products and ACD-SC databases were found to have lower binding free energy with 3CLpro than that of Ag7088. These structures have similar hydrophobicity to Ag7088. They have complementary electrostatic potential and hydrogen bond acceptor and donor with 3CLpro, showing that the strategy of anti-SARS drug design based on molecular docking and database screening is feasible.
基金ProjectsupportedbytheMinisterofScienceandTechnologyofChina (No .2 0 0 2AA2 3 10 11) ,theNationalNaturalScienceFoundationofChina (No .2 0 0 73 0 5 8) ,theScienceandTechnologyCommitteeofShanghai (No .0 2DJ14 0 13 ) ,ChineseAcademyofSciences NationalCentero
文摘For Histone Deacetylase (HDAC) Inhibitor, four 3D-QSAR models for four types of different activities,were constructed. The cross-validated q 2 value of CoMFA Model 1 is 0.624 and the noncross-validated r 2 value is 0.939. The cross-validated q 2 value of Model 2 for training set is 0.652 and the noncross-validated r 2 value is 0.963. The cross-validated q 2 value for Model 3 is 0.713,with noncross-validated r 2 value 0.947. The cross-validated q 2 value for Model 4 is 0.566 with noncross-validated r 2 value 0.959. Their predicted abilities were validated by different test sets which did not include in training set. Then the relationship between substituents and activities was analyzed by using these models and the main influence elements in different positions (positions 8 and 14) were found. The polar donor electron group of position 8 could increase the activity of inhibition of HDAC,because it could form chelation with the catalytic Zn. Suitable bulk and positive groups at position 14 are favorable to anti-HDAC activity. These models could well interpret the relationship between inhibition activity and apicidin structure affording us important information for structure-based drug design.
