Exploration of Novel Xanthine Oxidase Inhibitors Based on 1,6-Dihydropyrimidine-5-Carboxylic Acids by an Integrated in Silico Study.
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ABSTRACT:
SUBMITTER: Zhai N
PROVIDER: S-EPMC8348919 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In the present study, in silico predictions and molecular docking were performed on five clerodane diterpenes (1-5) from Polyalthia longifolia seeds to evaluate their potential as xanthine oxidase (XO) inhibitors. The initial screening was conducted by target prediction using TargetNet web server application and only compounds 3 and 4 showed a potential interaction with XO. Compounds 3 and 4 were subsequently subjected to in silico analyses on XO protein structure (PDB: 1N5X) using Schrödinger Release 2020-3 followed by structural modeling & molecular simulation studies to confirm the initial prediction result and identify the binding mode of these compounds to the XO. Molecular docking results revealed that compounds 3 (-37.3 kcal/mol) and 4 (-32.0 kcal/mol) binds more stably to XO than the reference drug allopurinol (-27.0 kcal/mol). Interestingly, two residues Glu 802 and Thr 1010 were observed as the two main H-bond binding sites for both tested compounds and the allopurinol. The center scaffold of allopurinol was positioned by some π-π stacking with Phe 914 and Phe 1009, while that of compounds 3 and 4 were supported by many hydrophobic interactions mainly with Leu 648, Phe 649, Phe 1013, and Leu 1014. Additionally, the docking simulation predicted that the inhibitory effect of compounds 3 and 4 was mediated by creating H-bond with particularly Glu 802, which is a key amino acid for XO enzyme inhibition. Altogether, in vitro studies showed that compounds 3 and 4 had better inhibitory capacity against XO enzyme with IC50 values significantly (p < 0.001) lower than that of allopurinol. In short, the present study identified cleroda-4(18),13-dien-15,16-olide as novel potential XO inhibitors, which can be potentially used for the treatment of gout.
| S-EPMC8244894 | biostudies-literature
Project description:Xanthine oxidase activation occurs in sepsis and results in the generation of uric acid (UrAc) and reactive oxygen species (ROS). We aimed to evaluate the effect of xanthine oxidase inhibitors (XOis) in rats stimulated with lipopolysaccharide (LPS). LPS (10 mg/kg) was administered intraperitoneally (i.p.) immediately after allopurinol (Alo, 2 mg/kg) or febuxostat (Feb, 1 mg/kg) every 24 h for 3 days. To increase UrAc levels, oxonic acid (Oxo) was administered by gavage (750 mg/kg per day) for 5 days. Animals were divided into the following 10 groups (n = 6 each): (1) Control, (2) Alo, (3) Feb, (4) LPS, (5) LPSAlo, (6) LPSFeb, (7) Oxo, (8) OxoLPS, (9) OxoLPSAlo, and (10) OxoLPSFeb. Feb with or without Oxo did not aggravate sepsis. LPS administration (with or without Oxo) significantly decreased the creatinine clearance (ClCr) in LPSAlo (60%, P < 0.01) versus LPS (44%, P < 0.05) and LPSFeb (35%, P < 0.05). Furthermore, a significant increase in mortality was observed with LPSAlo (28/34, 82%) compared to LPS treatment alone (10/16, 63%) and LPSFeb (11/17, 65%, P < 0.05). In addition, increased levels of thiobarbituric acid reactive substances (TBARS), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 were observed at 72 h compared to the groups that received LPS and LPSFeb with or without Oxo. In this study, coadministration of Alo in LPS-induced experimental sepsis aggravated septic shock, leading to mortality, renal function impairment, and high ROS and proinflammatory IL levels. In contrast, administration of Feb did not potentiate sepsis, probably because it did not interfere with other metabolic events.
| S-EPMC5967155 | biostudies-literature
Project description:Background:Xanthine oxidase is an important enzyme of purine catabolism pathway and has been associated directly in pathogenesis of gout and indirectly in many pathological conditions like cancer, diabetes and metabolic syndrome. In this research rutin, a bioactive flavonoid was explored to determine the capability of itself and its derivatives to inhibit xanthine oxidase. Objective:To develop new xanthine oxidase inhibitors from natural constituents along with antioxidant potential. Method:In this report, we designed and synthesized rutin derivatives hybridized with hydrazines to form hydrazides and natural acids to form ester linkage with the help of molecular docking. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential. Results:The enzyme kinetic studies performed on rutin derivatives showed a potential inhibitory effect on XO ability in competitive manner with IC50 value ranging from 04.708 to 19.377 µM and RU3a 3 was revealed as most active derivative. Molecular simulation revealed that new rutin derivatives interacted with the amino acid residues PHE798, GLN1194, ARG912, GLN 767, ALA1078 and MET1038 positioned inside the binding site of XO. Results of antioxidant activity revealed that all the derivatives showed very good antioxidant potential. Conclusion:Taking advantage of molecular docking, this hybridization of two natural constituent could lead to desirable xanthine oxidase inhibitors with improved activity.
| S-EPMC6661775 | biostudies-literature
Project description:BackgroundHesperitin, a naturally occurring flavonoid was hybridized with phenolic acids to evaluate its potential to inhibit the activity of xanthine oxidase (XO), a key enzyme which catalyses xanthine to uric acid which is found to be associated with gout and many life style related disorders.ObjectiveTo develop new xanthine oxidase inhibitors from natural constituents along with antioxidant potential.MethodIn this report, we designed and synthesized hesperitin derivatives hybridized with natural phenolic acids to form ester linkage with the help of molecular docking. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential.ResultsThe in vitro xanthine oxidase inhibitory activity and enzyme kinetics studies showed that hesperitin derivatives displayed a potential inhibition against XO in competitive manner with IC50 value ranging from 9.0 to 23.15 µM and HET4 was revealed as most active derivative. Molecular simulation revealed that new hesperitin derivatives interacted with the amino acid residues SER1080, PHE798, GLN1194, ARG912, THR1083, ALA1078 and MET1038 located within the active cavity of XO. Results of antioxidant activity revealed that all the derivatives showed very good antioxidant potential.ConclusionTaking advantage of molecular docking, this hybridization of two natural constituent could lead to desirable xanthine oxidase inhibitors with improved activity.
| S-EPMC6661729 | biostudies-literature
Project description:BackgroundHypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generate atherosclerosis and cholesterol crystals. β-Hydroxy β-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced cholesterol levels, most of them have failed to meet potential drug candidates' requirements. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR in a wet lab setup.MethodsOut of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were selected based on the IC50 values reported in in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-silico ADMET analysis was carried out to explore their pharmacokinetic properties, followed by toxicity prediction through ProTox-II.ResultsThe molecular docking of amentoflavone (GOLD score 70.54, ∆G calc. = - 10.4 Kcal/mol) and ganomycin I (GOLD score 59.61, ∆G calc. = - 6.8 Kcal/mol) displayed that the drug has effectively bound at the competitive site of XO and HMGR, respectively. Besides, 6-paradol and selgin could be potential drug candidates inhibiting XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl (6' → 1″)-O-α-D-glucopyranoside could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis has shown that these sixteen metabolites were optimal within the categorical range compared to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through ProTox-II revealed that 6-gingerol, ganoleucoin K, and ganoleucoin Z are toxic for human use.ConclusionThis computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.
| S-EPMC7775628 | biostudies-literature
Project description:Dihydropyrimidine derivatives possess many biological activities due to presence of pyrimidine ring structure in various nucleic acids, vitamins, coenzymes, uric acid and their derivatives. They have possessed broad spectrum actions like antibacterial, antifungal, antiviral, anticancer and antihypertensive etc. Before synthesis of compounds, it is good to predict biological activity using in silico methods. Here, we have selected some of N (3a-f) and O (4a-f) mannich bases of dihydro pyrimidine derivatives emphasized on histone deacetylase 4 (HDAC-4) inhibitions activity. We have used the different software tools like Lipinski's rule of five; pass online; osiris property explorer and docking studies to predict anti cancer activity. All the selected compounds exhibited potential drug like molecule with anti cancer activity. Among all compound the substitution with methoxy group (3c) exhibited more drugs like property and substation with hydrogens (4a) showed high anti neoplastic activity; whereas substitution with dichloro groups (4e) showed more drug docking scores. These were compared with standard drugs tamoxifen and 5-flourouracil. The approach of predicting anticancer activity using in silico method may be more useful to select and synthesis novel compounds in research as well as in industry.
| S-EPMC5639823 | biostudies-literature
Project description:Polygala plants contain a large number of xanthones with good physiological activities. In our previous work, 18 xanthones were isolated from Polygala crotalarioides. Extented study of the chemical composition of the other species Polygala sibirica led to the separation of two new xanthones-3-hydroxy-1,2,6,7,8-pentamethoxy xanthone (A) and 6-O-?-d-glucopyranosyl-1,7-dimethoxy xanthone (C)-together with 14 known xanthones. Among them, some xanthones have a certain xanthine oxidase (XO) inhibitory activity. Furthemore, 14 xanthones as XO inhibitors were selected to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. The CoMFA model predicted a q² value of 0.613 and an r² value of 0.997. The best CoMSIA model predicted a q² value of 0.608 and an r² value of 0.997 based on a combination of steric, electrostatic, and hydrophobic effects. The analysis of the contour maps from each model provided insight into the structural requirements for the development of more active XO inhibitors.
| S-EPMC6017007 | biostudies-literature
Project description:Dryopteris crassirhizoma rhizomes are used as a traditional medicine in Asia. The EtOAc extract of these roots has shown potent xanthine oxidase (XO) inhibitory activity. However, the main phloroglucinols in D. crassirhizoma rhizomes have not been analyzed. Thus, we investigated the major constituents responsible for this effect. Bioassay-guided purification isolated four compounds: flavaspidic acid AP (1), flavaspidic acid AB (2), flavaspidic acid PB (3), and flavaspidic acid BB (4). Among these, 1 showed the most potent inhibitory activity with a half-maximal inhibitory concentration (IC50) value of 6.3 µM, similar to that of allopurinol (IC50 = 5.7 µM) and better than that of oxypurinol (IC50 = 43.1 µM), which are XO inhibitors. A comparative activity screen indicated that the acetyl group at C3 and C3' is crucial for XO inhibition. For example, 1 showed nearly 4-fold higher efficacy than 4 (IC50 = 20.9 µM). Representative inhibitors (1-4) in the rhizomes of D. crassirhizoma showed reversible and noncompetitive inhibition toward XO. Furthermore, the potent inhibitors were shown to be present in high quantities in the rhizomes by a UPLC-QTOF-MS analysis. Therefore, the rhizomes of D. crassirhizoma could be used to develop nutraceuticals and medicines for the treatment of gout.
| S-EPMC7796287 | biostudies-literature
Project description:Xanthine oxidase (XO) has been well-recognized as a validated target for the treatment of hyperuricemia and gout. Currently, there are two drugs in clinical use that shut down XO overactivity, allopurinol and febuxostat; however, detrimental side effects restrict their applications. Propolis is a unique natural adhesive biomass of structurally variable and biologically active metabolites that exert remarkable health benefits. Moreover, combination drug therapy has become a promising pharmacotherapeutic strategy directed for reformulating existing drugs into new combination entities with potentiating therapeutic impacts. In this study, computer-aided molecular docking and MD simulations accompanied by biochemical testing were used for mining novel pharmacologically active chemical entities from Egyptian propolis to combat hyperuricemia. Further, with a view to decrease the potential toxicity of synthetic drugs and enhance efficacy, propolis hits were subjected to combination analysis with each of allopurinol and febuxostat. More specifically, Glide docking was utilized for a structure-based virtual screening of in-house datasets comprising various Egyptian propolis metabolites. Rosmarinic acid, luteolin, techtochrysin and isoferulic acid were the most promising virtual hits. In vitro XO inhibitory assays demonstrated the ability of these hits to significantly inhibit XO in a dose-dependent manner. Molecular docking and MD simulations revealed a cooperative binding mode between the discovered hits and standard XO inhibitors within the active site. Subsequently, the most promising hits were tested in a fixed-ratio combination setting with allopurinol and febuxostat separately to assess their combined effects on XO catalytic inhibition. The binary combination of each techtochrysin and rosmarinic acid with febuxostat displayed maximal synergy at lower effect levels. In contrast, individually, techtochrysin and rosmarinic acid with allopurinol cooperated synergistically at high dose levels. Taken together, the suggested strategy seems imperative to ensure a steady supply of new therapeutic options sourced from Egyptian propolis to regress the development of hyperuricemia.
| S-EPMC8979054 | biostudies-literature
Project description:As previous studies have reported finding an association between hyperuricemia and the development of cardiovascular and chronic kidney disease, hyperuricemia is thought to be an independent risk factor for hypertension and diabetic mellitus. However, we have not been able to determine whether the use of xanthine oxidase inhibitors can reduce cardiovascular disease. The present study used the longitudinal data of the Fukushima Cohort Study to investigate the relationship between the use of xanthine oxidase inhibitors and cardiovascular events in patients with cardiovascular risks. During the 3-year period between 2012 and 2014, a total of 2724 subjects were enrolled in the study and followed. A total of 2501 subjects had hypertension, diabetic mellitus, dyslipidemia, or chronic kidney disease, and were identified as having cardiovascular risks. The effects of xanthine oxidase inhibitor use on the development of cardiovascular events was evaluated in these patients using a time to event analysis. During the observational periods (median 2.7 years), the incidence of cardiovascular events was 20.7 in subjects with xanthine oxidase inhibitor and 11.2 (/1000 person-years, respectively) in those without. Although a univariate Cox regression analysis showed that the risk of cardiovascular events was significantly higher in subjects administered xanthine oxidase inhibitors (HR = 1.87, 95% CI 1.19-2.94, p = 0.007), the risk was significantly lower in subjects administered a xanthine oxidase inhibitor after adjustment for covariates (HR = 0.48, 95% CI 0.26-0.91; p = 0.024) compared to those without. Xanthine oxidase inhibitor use was associated with reduced risk of cardiovascular disease in patients with cardiovascular risk factors.
| S-EPMC7809289 | biostudies-literature