Identification of novel NAD(P)H dehydrogenase [quinone] 1 antagonist using computational approaches.
01 Feb 2020-Journal of Biomolecular Structure & Dynamics (Taylor & Francis)-Vol. 38, Iss: 3, pp 682-696
TL;DR: The results of induced fit docking and prime/MM-GBSA suggest that leads AN-153/J117103 and AT-138/KB09997 binding with the catalytic site suggests potential of this compound to treat cancer.
Abstract: NAD(P)H: quinone oxidoreductase 1 (NQO1) inhibitors are proved as promising therapeutic agents against cancer. This study is to determine potent NAD(P)H-dependent NQO1 inhibitors with new scaffold. Pharmacophore-based three-dimensional (3D) QSAR model has been built based on 45 NQO1 inhibitors reported in the literature. The structure-function correlation coefficient graph represents the relationship between phase activity and phase predicted activity for training and test sets. A QSAR model statistics shows the excellent correlation of the generated model. Pharmacophore hypothesis (AARR) yielded a statistically significant 3D QSASR model with a correlation coefficient of r2 = 0.99 as well as an excellent predictive power. From the analysis of pharmacophore-based virtual screening using by SPEC database, 4093 hits were obtained and were further filtered using virtual screening filters (HTVS, SP, XP) through structure based molecular docking. Based on glide energy and docking score, seven lead compounds show better binding affinity compared to the co-crystal inhibitor. The results of induced fit docking and prime/MM-GBSA suggest that leads AN-153/J117103 and AT-138/KB09997 binding with the catalytic site. Further, to understanding the stability of identified lead compounds MD simulations were done. The lead AN-153/J117103 showed the strong binding stable of the protein-ligand complex. Also the computed drug likeness reveals potential of this compound to treat cancer. AbbreviationsNQO1NAD(P)H-quinine oxidoreductase 1CPHcommon pharmacophore hypothesisPLSpartial least squireHBDhydrogen bond donorSDstandard deviationXPextra precisionIFDinduced fit dockingMM-GBSAmolecular mechanics generalized born surface areaMDSmolecular dynamics simulationRMSDroot mean square deviationRMSFroot mean square fluctuationRMSEroot mean square errorADMEabsorption distribution metabolism excretionsCommunicated by Ramaswamy H. Sarma.
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TL;DR: NQO1 emerges as a good model to investigate loss of function mechanisms in genetic diseases as well as to improve strategies to discriminate between neutral and pathogenic variants in genome-wide sequencing studies.
60 citations
Journal Article•
TL;DR: Comparisons between pancreatic adenocarcinoma, pancreatic cancer cell lines, normal pancreas, and chronic pancreatitis have identified genes that are selectively expressed in the neoplastic epithelium of pancreatic adsorption.
Abstract: The molecular basis of pancreatic cancer is not understood. Previous attempts to determine the specific genes expressed in pancreatic cancer have been hampered by similarities between adenocarcinoma and chronic pancreatitis. In the current study, microarrays (Affymetrix) were used to profile gene expression in pancreatic adenocarcinoma (10), pancreatic cancer cell lines (7), chronic pancreatitis (5), and normal pancreas (5). Molecular profiling indicated a large number of genes differentially expressed between pancreatic cancer and normal pancreas but many fewer differences between pancreatic cancer and chronic pancreatitis, likely because of the shared stromal influences in the two diseases. To specifically identify genes expressed in neoplastic epithelium, we selected genes more highly expressed (>2-fold, p < 0.01) in adenocarcinoma compared with both normal pancreas and chronic pancreatitis and which were also highly expressed in pancreatic cancer cell lines. This strategy yielded 158 genes, of which 124 were not previously associated with pancreatic cancer. Quantitative-reverse transcription-PCR for two molecules, S100P and 14-3-3sigma, validated the microarray data. Support for the success of the neoplastic cell gene expression identification strategy was obtained by immunocytochemical localization of four representative genes, 14-3-3sigma, S100P, S100A6, and beta4 integrin, to neoplastic cells in pancreatic tumors. Thus, comparisons between pancreatic adenocarcinoma, pancreatic cancer cell lines, normal pancreas, and chronic pancreatitis have identified genes that are selectively expressed in the neoplastic epithelium of pancreatic adenocarcinoma. These data provide new insights into the molecular pathology of pancreatic cancer that may be useful for detection, diagnosis, and treatment.
40 citations
References
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Journal Article•
TL;DR: In this article, microarray data were used to profile gene expression in pancreatic adenocarcinoma (10), pancreatic cancer cell lines (7), chronic pancreatitis (5), and normal pancreas (5).
Abstract: The molecular basis of pancreatic cancer is not understood. Previous attempts to determine the specific genes expressed in pancreatic cancer have been hampered by similarities between adenocarcinoma and chronic pancreatitis. In the current study, microarrays (Affymetrix) were used to profile gene expression in pancreatic adenocarcinoma (10), pancreatic cancer cell lines (7), chronic pancreatitis (5), and normal pancreas (5). Molecular profiling indicated a large number of genes differentially expressed between pancreatic cancer and normal pancreas but many fewer differences between pancreatic cancer and chronic pancreatitis, likely because of the shared stromal influences in the two diseases. To specifically identify genes expressed in neoplastic epithelium, we selected genes more highly expressed (>2-fold, p < 0.01) in adenocarcinoma compared with both normal pancreas and chronic pancreatitis and which were also highly expressed in pancreatic cancer cell lines. This strategy yielded 158 genes, of which 124 were not previously associated with pancreatic cancer. Quantitative-reverse transcription-PCR for two molecules, S100P and 14-3-3sigma, validated the microarray data. Support for the success of the neoplastic cell gene expression identification strategy was obtained by immunocytochemical localization of four representative genes, 14-3-3sigma, S100P, S100A6, and beta4 integrin, to neoplastic cells in pancreatic tumors. Thus, comparisons between pancreatic adenocarcinoma, pancreatic cancer cell lines, normal pancreas, and chronic pancreatitis have identified genes that are selectively expressed in the neoplastic epithelium of pancreatic adenocarcinoma. These data provide new insights into the molecular pathology of pancreatic cancer that may be useful for detection, diagnosis, and treatment.
554 citations
TL;DR: The ability of molecular docking, using the program Glide and an MM-GBSA postdocking scoring protocol, to correctly rank a number of congeneric kinase inhibitors was assessed and suggests that this may be useful for the design of inhibitors in the lead optimization phase of drug discovery.
Abstract: The ability of molecular docking, using the program Glide and an MM-GBSA postdocking scoring protocol, to correctly rank a number of congeneric kinase inhibitors was assessed. The approach was successful for the cases considered and suggests that this may be useful for the design of inhibitors in the lead optimization phase of drug discovery.
547 citations
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TL;DR: DT diaphorase is a flavin adenine dinucleotide (FAD)-eontaining flavoprotein, which catalyzes the oxidation of NADH and NADPH by various dyes and quinones with a maximal velocity of the order of 10 7 moles per mole of flavin per minute.
Abstract: Publisher Summary DT diaphorase is widely distributed in the animal kingdom, and is a flavin adenine dinucleotide (FAD)-eontaining flavoprotein, which catalyzes the oxidation of NADH and NADPH by various dyes and quinones with a maximal velocity of the order of 10 7 moles per mole of flavin per minute. Bovine serum albumin (0.07%), polyvinylpyrrolidone (5%), and certain nonionic detergents such as Tween-20 or -60 (0.2%) are activators of DT diaphorase; the concentrations in parentheses are those required for maximal activation. The activation is reversible and implies both an elevation of the V max of the enzyme and an increase of its affinity for NADH and NADPH. The need for an activator increases during the purification and storage of the enzyme, probably because of the removal or destruction of a naturally occurring activator. Various electron acceptors for DT diaphorase are listed. 2, 6-Diehlorophenolindophenol (DCPIP) and certain benzo- and naphthoquinones are the best electron acceptors, whereas methylene blue and ferricyanide are relatively inefficient, and cytochromes c and b 5 are practically inactive as electron acceptors. The chapter also describes the assay and purification procedure of DT diaphorase, and discusses the DT diaphorase relation to other diaphorases and related enzymes.
526 citations
"Identification of novel NAD(P)H deh..." refers methods in this paper
...NQO1 is a flavoprotein that catalyzes the obligatory two-electron reduction of quinone to hydroquinone using NADP or NADPH co-factor (Atia, Alrawaiq, & Azman, 2014; Ernster, 1967; Ernster et al., 1958; L opez-Lira et al., 2018; Ross, Beall, Siegel, Traver, & Gustafson, 1996)....
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TL;DR: Pharmacophore modeling and 3D database searching are now recognized as integral components of lead discovery and lead optimization, and the continuing need for improved pharmacophore‐based tools has driven the development of PHASE.
Abstract: Pharmacophore modeling and 3D database searching are now recognized as integral components of lead discovery and lead optimization, and the continuing need for improved pharmacophore-based tools has driven the development of PHASE. By employing a novel, tree-based partitioning algorithm, PHASE exhaustively identifies spatial arrangements of functional groups that are common and essential to the biologic activity of a set of high affinity ligands. These pharmacophore hypotheses are validated in a number of ways, including their ability to: (i) rationalize the binding affinities of a training set of molecules of varying activity, (ii) successfully predict the affinities of a test set of molecules, and (iii) selectively retrieve known actives from a database of drug-like molecules. In addition, PHASE uniquely offers the ability to distinguish multiple binding modes through a bi-directional clustering approach applied to bit string representations of the ligand/hypothesis space.
515 citations
"Identification of novel NAD(P)H deh..." refers background or methods in this paper
...PHASE 6.6 (Dixon et al., 2006) contains a built-in set of six pharmacophoric features, hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic group (H), negatively ionizable (N), positively ionizable (P), and aromatic ring (R)....
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...All the minimized conformers were filtered using a relative energy window of 10 kcal mol 1 and a minimum atom deviation of 1.0 Å (Dixon et al., 2006; Dixon, Smondyrev, & Rao, 2006)....
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TL;DR: The redox sensitivity of NQO1 transcription occurs through a cis-acting antioxidant response element (ARE) located within the regulatory region of the mouse, rat and human genes, which recruits the positively acting basic leucine zipper transcription factor NF-E2 p45-related factor 2 (Nrf2).
Abstract: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a key enzyme involved in defence against reactive forms of oxygen and inhibition of neoplasia. Under conditions of oxidative stress, expression of NQO1 is induced, and the resulting increase in oxidoreductase protein provides the cell with multiple layers of protection against environmental insults. Firstly, the catalytic activity of NQO1 is directed towards the complete reduction and detoxication of highly reactive quinones. Secondly, the oxidoreductase maintains the endogenous lipid-soluble antioxidants, alpha-tocopherol-hydroquinone and ubiquinol in their reduced and active forms. Thirdly, NQO1 is required for the stabilisation of p53 protein in response to DNA-damaging stimuli, and it thereby influences cell fate decisions. In view of the anticarcinogenic actions of NQO1, an understanding of the mechanisms that govern its expression is desirable. The redox sensitivity of NQO1 transcription occurs through a cis-acting antioxidant response element (ARE) located within the regulatory region of the mouse, rat and human genes. This element recruits the positively acting basic leucine zipper (bZip) transcription factor NF-E2 p45-related factor 2 (Nrf2). Under normal constitutive conditions, Nrf2 associates with the cytoskeletal-binding protein Keap1, which regulates the subcellular distribution of the bZip factor and also targets it for proteasome-dependent degradation. Oxidative stress inhibits the Nrf2-Keap1 interaction, thus promoting nuclear accumulation of the transcription factor and transactivation of NQO1 and other ARE-driven genes. Mouse, rat and human NQO1 can also be induced by planar aromatic hydrocarbons through a cis-acting xenobiotic response element (XRE) located in their gene promoters. The XRE recruits the arylhydrocarbon receptor (AhR) and AhR nuclear translocator. Cross-talk may occur between Nrf2 and AhR, but the details of this process remain to be elucidated.
356 citations
"Identification of novel NAD(P)H deh..." refers background in this paper
...Under both normal and oxidative stress conditions, antioxidant response element (ARE) regulates the gene and NQO1 expression in various tissues (Nioi & Hayes, 2004)....
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