Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Phenylpropanoids and flavonoids from Phlomis kurdica as inhibitors of human lactate dehydrogenase.

ABSTRACT: Two flavonoids, jaceosidin 7-O-?-d-glucopyranosyl-(1?2)-?-d-glucopyranoside (1) and hispidulin 7-O-?-d-glucopyranosyl-(1?2)-?-d-glucopyranoside (2), and one phenylpropanoid, 3,3'-dimethyl-lunariifolioside (3), along with 11 known compounds (4-14), were isolated from the aerial parts of Phlomis kurdica growing in Jordan. Structures of 1-3 were elucidated on the basis of spectroscopic data. These isolated compounds were assayed for their inhibitory activity against isoform 5 of human lactate dehydrogenase. Compound 4, luteolin 7-O-?-d-glucopyranoside, showed an IC50 value comparable to that of galloflavin, used as reference compound. Docking studies were carried out to hypothesize the interaction mode of compound 4 in the enzyme active site.

SUBMITTER: Bader A

PROVIDER: S-EPMC4466035 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Phenylpropanoids and flavonoids from Phlomis kurdica as inhibitors of human lactate dehydrogenase.

Bader Ammar A Tuccinardi Tiziano T Granchi Carlotta C Martinelli Adriano A Macchia Marco M Minutolo Filippo F De Tommasi Nunziatina N Braca Alessandra A

Phytochemistry 20150415

Two flavonoids, jaceosidin 7-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranoside (1) and hispidulin 7-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranoside (2), and one phenylpropanoid, 3,3'-dimethyl-lunariifolioside (3), along with 11 known compounds (4-14), were isolated from the aerial parts of Phlomis kurdica growing in Jordan. Structures of 1-3 were elucidated on the basis of spectroscopic data. These isolated compounds were assayed for their inhibitory activity against isoform 5 of human lactate dehyd ...[more]

PMID: 25890391

Similar Datasets

Human lactate dehydrogenase a inhibitors: a molecular dynamics investigation.

Project description:Lactate dehydrogenase A (LDHA) is an important enzyme in fermentative glycolysis, generating most energy for cancer cells that rely on anaerobic respiration even under normal oxygen concentrations. This renders LDHA a promising molecular target for the treatment of various cancers. Several efforts have been made recently to develop LDHA inhibitors with nanomolar inhibition and cellular activity, some of which have been studied in complex with the enzyme by X-ray crystallography. In this work, we present a molecular dynamics (MD) study of the binding interactions of selected ligands with human LDHA. Conventional MD simulations demonstrate different binding dynamics of inhibitors with similar binding affinities, whereas steered MD simulations yield discrimination of selected LDHA inhibitors with qualitative correlation between the in silico unbinding difficulty and the experimental binding strength. Further, our results have been used to clarify ambiguities in the binding modes of two well-known LDHA inhibitors.

| S-EPMC3895040 | biostudies-literature

Search for Human Lactate Dehydrogenase A Inhibitors Using Structure-Based Modeling.

Project description:The human lactate dehydrogenase isoform A plays an important role in the anaerobic metabolism of tumour cells and therefore constitutes an attractive target in the oncology field. Full-atom models of lactate dehydrogenase A (in complex with NADH and in the apo form) have been generated to enable structure-based design of novel inhibitors competing with pyruvate and NADH. The structural criteria for the selection of potential inhibitors were established, and virtual screening of a library of low-molecular-weight compounds was performed. A potential inhibitor, STK381370, was identified whose docking pose was stabilized through additional interactions with the loop 96-111 providing for the transition from the open to the closed conformation.

| S-EPMC4463413 | biostudies-literature

Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice.

Project description:A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 μM lactate IC50 in a MiaPaca2 cell line. Optimization of the series led to 29, a potent cell active molecule (MiaPaca2 IC50 = 0.67 μM) that also possessed good exposure when dosed orally to mice.

| S-EPMC5066143 | biostudies-literature

Identification of human D lactate dehydrogenase deficiency.

Project description:Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this with the identification of two different homozygous variants resulting in enzymatic loss-of-function in LDHD, encoding lactate dehydrogenase D, in two unrelated patients with elevated D-lactate urinary excretion and plasma concentrations. We establish the role of LDHD by demonstrating that LDHD loss-of-function in zebrafish results in increased concentrations of D-lactate. D-lactate levels are rescued by wildtype LDHD but not by patients' variant LDHD, confirming these variants' loss-of-function effect. This work provides the first in vivo evidence that LDHD is responsible for human D-lactate metabolism. This broadens the differential diagnosis of D-lactic acidosis, an increasingly recognized complication of short bowel syndrome with unpredictable onset and severity. With the expanding incidence of intestinal resection for disease or obesity, the elucidation of this metabolic pathway may have relevance for those patients with D-lactic acidosis.

| S-EPMC6443703 | biostudies-literature

Optimization of ether and aniline based inhibitors of lactate dehydrogenase.

Project description:Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.

| S-EPMC8113097 | biostudies-literature

Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria.

Project description:Both glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) influence the endogenous synthesis of oxalate and are clinically validated targets for treatment of primary hyperoxaluria (PH). We investigated whether dual inhibition of GO and LDHA may provide advantage over single agents in treating PH. Utilizing a structure-based drug design (SBDD) approach, we developed a series of novel, potent, dual GO/LDHA inhibitors. X-ray crystal structures of compound 15 bound to individual GO and LDHA proteins validated our SBDD strategy. Dual inhibitor 7 demonstrated an IC50 of 88 nM for oxalate reduction in an Agxt-knockdown mouse hepatocyte assay. Limited by poor liver exposure, this series of dual inhibitors failed to demonstrate significant PD modulation in an in vivo mouse model. This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.

| S-EPMC8274068 | biostudies-literature

Novel lactate dehydrogenase inhibitors with in vivo efficacy against Cryptosporidium parvum.

Project description:Cryptosporidium parvum is a highly prevalent zoonotic and anthroponotic protozoan parasite that causes a diarrheal syndrome in children and neonatal livestock, culminating in growth retardation and mortalities. Despite the high prevalence of C. parvum, there are no fully effective and safe drugs for treating infections, and there is no vaccine. We have previously reported that the bacterial-like C. parvum lactate dehydrogenase (CpLDH) enzyme is essential for survival, virulence and growth of C. parvum in vitro and in vivo. In the present study, we screened compound libraries and identified inhibitors against the enzymatic activity of recombinant CpLDH protein in vitro. We tested the inhibitors for anti-Cryptosporidium effect using in vitro infection assays of HCT-8 cells monolayers and identified compounds NSC158011 and NSC10447 that inhibited the proliferation of intracellular C. parvum in vitro, with IC50 values of 14.88 and 72.65 μM, respectively. At doses tolerable in mice, we found that both NSC158011 and NSC10447 consistently significantly reduced the shedding of C. parvum oocysts in infected immunocompromised mice's feces, and prevented intestinal villous atrophy as well as mucosal erosion due to C. parvum. Together, our findings have unveiled promising anti-Cryptosporidium drug candidates that can be explored further for the development of the much needed novel therapeutic agents against C. parvum infections.

| S-EPMC6687188 | biostudies-literature

Pyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties.

Project description:Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of reduced nicotinamide adenine dinucleotide as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo, possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, in vitro drug-target residence times, and in vivo PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition in vivo. The lead compounds, named NCATS-SM1440 (43) and NCATS-SM1441 (52), possess desirable attributes for further studying the effect of in vivo LDH inhibition.

| S-EPMC7830743 | biostudies-literature

Identification of New Structural Fragments for the Design of Lactate Dehydrogenase A Inhibitors.

Project description:Human lactate dehydrogenase A plays an important role in the glucose metabolism of tumor cells and constitutes an attractive target for chemotherapy. Molecular fragments able to bind in the active site of this enzyme and form hydrogen bonds with the Arg168 guanidinium group, as well as additional interactions with the loop 96-111 in the closed conformation, have been identified by virtual screening of sulfonates and experimental testing of their inhibitory effect. The sulfo group can occupy a similar position as the carboxyl group of the substrate and its structural analogs, whereas the benzothiazole group attached via a linker can be located in the coenzyme (NADH) binding site. Thus, the value of merging individual structural elements of the inhibitor by a linker was demonstrated and ways of further structural modification for the design of more effective inhibitors of lactate dehydrogenase A were established.

| S-EPMC5081701 | biostudies-literature

Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors.

Project description:Altered metabolism is a hallmark of cancer; however, it has been difficult to specifically target metabolism in cancer for therapeutic benefit. Cancers with genetically defined defects in metabolic enzymes constitute a subset of cancers where targeting metabolism is potentially accessible. Hürthle cell carcinoma of the thyroid (HTC) tumors frequently harbor deleterious mitochondrial DNA (mtDNA) mutations in subunits of complex I of the mitochondrial electron transport chain (ETC). Previous work has shown that HTC models with deleterious mtDNA mutations exhibit mitochondrial ETC defects that expose lactate dehydrogenase (LDH) as a therapeutic vulnerability. Here, we performed forward genetic screens to identify mechanisms of resistance to small molecule LDH inhibitors. We identified two distinct mechanisms of resistance: upregulation of an LDH isoform and a compound-specific resistance mutation. Using these tools, we demonstrate that the anti-cancer activity of LDH inhibitors in cell line and xenograft models of complex I-mutant HTC is through on-target LDH inhibition.

| S-EPMC10557759 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data