Therapeutic Targets Database
BIDD Pharmainformatics Databases
 
   
 

 

Target Validation Information
TTD IDTTDS00080
Target NameDNA topoisomerase II    
Type of TargetSuccessful target    
Drug Potency against TargetQuinolonesIC50 = 0.2~4 g/ml[1]
NovobiocinIC50 = 10 nM[2]
DoxorubicinIC50 = 330 nM[3]
IdarubicinIC50 = 38 nM[4]
DoxorubicinIC50 = 66.3 nM[4]
DoxorubicinKi = 10000 nM[5]
GemifloxacinMIC50 = 0.002 ug/ml[6]
GarenoxacinMIC50 = 0.03 ug/ml[6]
LUPEOLIC50 = 10400 nM[7]
Olean-12-en-3beta,15alpha-diolIC50 = 17500 nM[7]
DEMETHYLZEYLASTERONEIC50 = 17600 nM[8]
TOPOSTATINIC50 = 4000 nM[9]
PIROXANTRONEIC50 = 4600 nM[10]
A-62176IC50 = 510 nM[11]
LOSOXANTRONEIC50 = 7300 nM[10]
Action against Disease ModelGatifloxacinFluoroquinolones are a class of synthetic antibacterial agents that were approved for ocular therapy in 1991 and have become popular therapy for the treatment and prevention of various ocular infections. These agents are synthetic, broad-spectr uM, rapidly bactericidal, and have good penetration into ocular tissues. Their main mechanism of action is the inhibition of bacterial enzymes needed for bacterial DNA synthesis. However, antibiotic resistance occurred swiftly to the earlier fluoroquinolones and better fluoroquinolones were needed. The fourth-generation fluoroquinolones, such as moxifloxacin and gatifloxacin, have enhanced activity against gram-positive bacteria while retaining potent activity against most gram-negative bacteria. These fourth-generation fluoroquinolones have improved penetration into the anterior chamber and have also demonstrated increased in vivo efficacy in several animal models of ocular infections. In addition, topical ophthalmic antibiotic products can deliver antibiotic concentrations directly to the eye that are thousands of times higher than their MICs. This article reviews published data describing the in vitro potency of moxifloxacin and its in vivo activity for treating and preventing experimental ocular infections.[12]
AmsacrineHERG-Lite monitors the expression of hERG at the cell surface in two different stable mammalian cell lines. One cell line acts as a biosensor for drugs that inhibit hERG trafficking, while the other predicts hERG blockers based on their ability to act as pharmacological chaperones. In this study, we have validated the HERG-Lite assay using a panel of 100 drugs: 50 hERG blockers and 50 nonblockers.HERG-Lite correctly predicted hERG risk for all 100 test compounds with no false positives or negatives. All 50 hERG blockers were detected as drugs with hERG risk in the HERG-Lite assay, and fell into two classes: B (for blocker) and C (for complex; block and trafficking inhibition).[13]
SparfloxacinThe in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk.[14]
PefloxacinThe in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk.[14]
EnoxacinThe in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk.[14]
FleroxacinThe in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk.[14]
NorfloxacinThe in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk.[14]
Ref 1Annu Rev Pharmacol Toxicol. 2005;45:529-64.The magic bullets and tuberculosis drug targets. To Reference
Ref 2Antimicrob Agents Chemother. 1996 Feb;40(2):473-6.Mode of action of GR122222X, a novel inhibitor of bacterial DNA gyrase. To Reference
Ref 3Registry of Cytotoxicity: List of 347 Chemicals Sorted by IC50 (mM) To Reference
Ref 4Mini Rev Med Chem. 2008 Apr;8(4):388-98.Mechanism of action of key enzymes associated with cancer propagation and their inhibition by various chemotherapeutic agents. To Reference
Ref 5Science. 2008 Jul 11;321(5886):263-6.Drug target identification using side-effect similarity. To Reference
Ref 6Expert Opin Investig Drugs. 2003 Mar;12(3):379-99.Novel antibacterial agents for the treatment of serious Gram-positive infections. To Reference
Ref 7J Nat Prod. 2001 Dec;64(12):1545-7.Screening of triterpenoids isolated from Phyllanthus flexuosus for DNA topoisomerase inhibitory activity. To Reference
Ref 8J Nat Prod. 2001 Oct;64(10):1294-6.Catalytic inhibition of topoisomerase IIalpha by demethylzeylasterone, a 6-oxophenolic triterpenoid from Kokoona zeylanica. To Reference
Ref 9J Nat Prod. 2001 Feb;64(2):204-7.Isoaurostatin, a novel topoisomerase inhibitor produced by Thermomonospora alba. To Reference
Ref 10Bioorg Med Chem. 2008 Apr 1;16(7):3959-68. Epub 2008 Jan 26.The structure-based design, synthesis and biological evaluation of DNA-binding bisintercalating bisanthrapyrazole anticancer compounds. To Reference
Ref 11J Med Chem. 1998 Oct 22;41(22):4273-8.Design of new topoisomerase II inhibitors based upon a quinobenzoxazine self-assembly model. To Reference
Ref 12Surv Ophthalmol. 2005 Nov;50 Suppl 1:S16-31.In vitro and in vivo potency of moxifloxacin and moxifloxacin ophthalmic solution 0.5%, a new topical fluoroquinolone. To Reference
Ref 13J Pharmacol Toxicol Methods. 2005 Jul-Aug;52(1):136-45.HERG-Lite: a novel comprehensive high-throughput screen for drug-induced hERG risk. To Reference
Ref 14Antimicrob Agents Chemother. 1999 Jun;43(6):1511-5.Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of fluoroquinolones in rats. To Reference



 

Welcome to sign our Guestbook.

If you find any error in data or bug in web service, please kindly report it to Dr. Zhu.


Dr. Chen Yuzong
Deputy Director of Center for Computational Science and Engineering
Professor in Department of Pharmacy
National University of Singapore, Singapore


All rights reserved.

 
   
           
 
Computer-aided Drug Design
About BIDD | Databases | Software | Teaching | Research |  Links

Department of Computational Science | National University of Singapore | Blk S17, 3 Science Drive 2, Singapore 117543