Improving the inhibitory activity of arylidenaminoguanidine compounds at the N-methyl-d-aspartate receptor complex from a recursive computational-experimental structure–activity relationship study

Ring, Joshua R.; Zheng, Fang; Haubner, Aaron; Littleton, John M.; Crooks, Peter A.

doi:10.1016/j.bmc.2013.01.051

Cited by 10 publications

(7 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The novel IAG compounds tested for inhibitory properties against the DNA polymerases were synthesized utilizing previously published procedures. 43 TMZ was purchased from Millipore Sigma (Burlington, MA). TMZ is an alkylating agent used in the treatment of cancer.…”

Section: Reagentsmentioning

confidence: 99%

Inhibition of Human DNA Polymerases Eta and Kappa by Indole-Derived Molecules Occurs through Distinct Mechanisms

et al. 2019

Self Cite

View full text Add to dashboard Cite

Overexpression of human DNA polymerase kappa (hpol κ) in glioblastoma is associated with shorter survival time and resistance to the alkylating agent temozolomide (TMZ), making it an attractive target for the development of small-molecule inhibitors. We previously reported on the development and characterization of indole barbituric acid-derived (IBA) inhibitors of translesion DNA synthesis polymerases (TLS pols). We have now identified a potent and selective inhibitor of hpol κ based on the indole-aminoguanidine (IAG) chemical scaffold. The most promising IAG analogue, IAG-10, exhibited greater inhibitory action against hpol κ than any other human Yfamily member, as well as pols from the A-, Band nd X-families. Inhibition of hpol κ by IAG analogues appears to proceed through a mechanism that is distinct from inhibition of hpol η based on changes in DNA binding affinity and nucleotide insertion kinetics. By way of comparison, both IAG and IBA analogues inhibited binary complex formation by hpol κ and ternary complex formation by hpol η. Decreasing the concentration of enzyme and DNA in the reaction mixture lowered the IC 50 value of IAG-10 to submicromolar values, consistent with inhibition of binary complex formation for hpol κ. Chemical footprinting experiments revealed that IAG-10 binds to a cleft between the finger, little finger, and N-clasp domains on hpol κ and that this likely disrupts the interaction between the N-clasp and the TLS pol core. Ln cell culture, IAG-10 potentiated the antiproliferative activity and DNA damaging effects of TMZ in hpol κ-proficient cells but not in hpol κ-deficient cells, indicative of a target-dependent effect. Mutagenic replication across alkylation damage increased in hpol κ-proficient cells treated with IAG-10, while no change in mutation frequency was observed for hpol κ-deficient cells. Ln summary, we developed a potent and selective small-molecule inhibitor of hpol κ that takes advantage of structural features unique to this TLS enzyme to potentiate TMZ, a standard-of-care drug used in the treatment of malignant brain tumors. Furthermore, the IAG scaffold represents a new chemical space for the exploration *

show abstract

Section: Reagentsmentioning

confidence: 99%

Inhibition of Human DNA Polymerases Eta and Kappa by Indole-Derived Molecules Occurs through Distinct Mechanisms

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Guanylhydrazone derivatives were obtained through the condensation reaction of benzaldehyde derivatives with aminoguanidine hydrochloride (7,8; see Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

Preliminary in vitro evaluation of the anti-proliferative activity of guanylhydrazone derivatives

et al. 2016

View full text Add to dashboard Cite

Preliminary in vitro evaluation of the anti-proliferative activity of guanylhydrazone derivativesGuanylhydrazones have shown promising antitumor activity in preclinical tumor models in several studies.In this study, we aimed at evaluating the cytotoxic eff ect of a series of synthetic guanylhydrazones. Diff erent human tumor cell lines, by including HCT-8 (colon carcinoma), MDA-MB-435 (melanoma) and SF-295 (glioblastoma) were continuous exposed to guanylhydrazone derivatives for 72 hours and growth inhibition of tumor cell lines and macrophages J774 was measured using tetrazolium salt (MTT) assay. Compounds 7, 11, 16 and 17 showed strong cytotoxic activity with IC 50 values lower than 10 μmol L -1 against four tumor cell lines. Among them, 7 was less toxic to non-tumor cells. Finally, obtained data suggest that guanylhydrazones may be regarded as potential lead compounds for the design of novel anticancer agents.

show abstract

“…In cheminformatics, it has been used in QSAR studies, to predict the activities of compounds from their structures and properties. 16–25 As an advanced data mining tool, neural network approach is particularly suitable for the cases where other techniques may not produce satisfactory predictive models.…”

Section: Resultsmentioning

confidence: 99%

“…Feed-forward, back-propagation-of-error networks were developed using a in-house neural network C program 17–20,23,25 Network weights (W ji (s)) for a neuron “j” receiving output from neuron “i” in the layer “s” were initially assigned random values between −0.5 and +0.5. The sigmoidal function was chosen as the transfer function that generates the output of a neuron from the weighted sum of inputs from the preceding layer of units.…”

Section: Methodsmentioning

confidence: 99%

“…The artificial neural network technique simulating brain function has been demonstrated to be an effective tool for data mining and used in many QSAR studies. 16–25 The impressive feature of the system includes its ability to model a wide set of functions, including linear and non-linear functions, without knowing the analytic forms in advance. Therefore, neural network approach is able to outperform linear modeling approach where non-linear feature is not negligible or dominant in a dataset.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Modeling in vitro inhibition of butyrylcholinesterase using molecular docking, multi-linear regression and artificial neural network approaches

Zheng

Zhan

Huang

et al. 2014

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Butyrylcholinesterase (BChE) has been an important protein used for development of anti-cocaine medication. Through computational design, BChE mutants with ~2000-fold improved catalytic efficiency against cocaine have been discovered in our lab. To study drug-enzyme interaction it is important to build mathematical model to predict molecular inhibitory activity against BChE. This report presents a neural network (NN) QSAR study, compared with multi-linear regression (MLR) and molecular docking, on a set of 93 small molecules that act as inhibitors of BChE by use of the inhibitory activities (pIC50 values) of the molecules as target values. The statistical results for the linear model built from docking generated energy descriptors were: r2 = 0.67, rmsd = 0.87, q2 = 0.65 and loormsd = 0.90; The statistical results for the ligand-based MLR model were: r2 = 0.89, rmsd = 0.51, q2 = 0.85 and loormsd = 0.58; the statistical results for the ligand-based NN model were the best: r2 = 0.95, rmsd = 0.33, q2 = 0.90 and loormsd = 0.48, demonstrating that the NN is powerful in analysis of a set of complicated data. As BChE is also an established drug target to develop new treatment for Alzheimer’s disease (AD). The developped QSAR models provide tools for rationalizing identification of potential BChE inhibitors or selection of compounds for synthesis in the discovery of novel effective inhibitors of BChE in the future.

show abstract

Improving the inhibitory activity of arylidenaminoguanidine compounds at the N-methyl-d-aspartate receptor complex from a recursive computational-experimental structure–activity relationship study

Cited by 10 publications

References 23 publications

Inhibition of Human DNA Polymerases Eta and Kappa by Indole-Derived Molecules Occurs through Distinct Mechanisms

Inhibition of Human DNA Polymerases Eta and Kappa by Indole-Derived Molecules Occurs through Distinct Mechanisms

Preliminary in vitro evaluation of the anti-proliferative activity of guanylhydrazone derivatives

Modeling in vitro inhibition of butyrylcholinesterase using molecular docking, multi-linear regression and artificial neural network approaches

Contact Info

Product

Resources

About