Engineering ‘Enzymelink’ for screening lead compounds to inhibit mPGES-1 while maintaining prostacyclin synthase activity

2021 ◽  
Author(s):  
Diana T Ruan ◽  
Nanhong Tang ◽  
Hironori Akasaka ◽  
Renzhong Lu ◽  
Ke-He Ruan
Keyword(s):  
Significant Degree ◽  
Hek293 Cells ◽  
Synthesis Methods ◽  
Compound Library ◽  
Lead Compounds ◽  
Cox 2 ◽  
Targeted Drug Discovery ◽  
Prostacyclin Synthase ◽  
Large Compound ◽  
Prostacyclin Synthesis

Aim: This study investigated our Enzymelinks, COX-2-10aa-mPGES-1 and COX-2-10aa-PGIS, as cellular cross-screening targets for quick identification of lead compounds to inhibit inflammatory PGE2 biosynthesis while maintaining prostacyclin synthesis. Methods: We integrated virtual and wet cross-screening using Enzymelinks to rapidly identify lead compounds from a large compound library. Results: From 380,000 compounds virtually cross-screened with the Enzymelinks, 1576 compounds were identified and used for wet cross-screening using HEK293 cells that overexpressed individual Enzymelinks as targets. The top 15 lead compounds that inhibited mPGES-1 activity were identified. The top compound that specifically inhibited inflammatory PGE2 biosynthesis alone without affecting COX-2 coupled to PGI2 synthase (PGIS) for PGI2 biosynthesis was obtained. Conclusion: Enzymelink technology could advance cyclooxygenase pathway-targeted drug discovery to a significant degree.

scholarly journals Autonomous molecule generation using reinforcement learning and docking to develop potential novel inhibitors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Woosung Jeon ◽  
Dongsup Kim
Keyword(s):  
Reinforcement Learning ◽  
Protein Structure ◽  
Virtual Screening ◽  
Computational Method ◽  
Target Protein ◽  
Training Data ◽  
Compound Library ◽  
Lead Compounds ◽  
Large Compound ◽  
Discoidin Domain Receptor 1

AbstractWe developed a computational method named Molecule Optimization by Reinforcement Learning and Docking (MORLD) that automatically generates and optimizes lead compounds by combining reinforcement learning and docking to develop predicted novel inhibitors. This model requires only a target protein structure and directly modifies ligand structures to obtain higher predicted binding affinity for the target protein without any other training data. Using MORLD, we were able to generate potential novel inhibitors against discoidin domain receptor 1 kinase (DDR1) in less than 2 days on a moderate computer. We also demonstrated MORLD’s ability to generate predicted novel agonists for the D4 dopamine receptor (D4DR) from scratch without virtual screening on an ultra large compound library. The free web server is available at http://morld.kaist.ac.kr.

Association of polymorphisms of PTGS2 and CYP8A1 with myocardial infarction

2009 ◽  
Vol 47 (3) ◽  
Author(s):  
Xiang Xie ◽  
Yi-tong Ma ◽  
Zhen-yan Fu ◽  
Yi-ning Yang ◽  
Xiang Ma ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Case Control Study ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Case Control ◽  
Chinese Case ◽  
Cox 2 ◽  
Prostacyclin Synthase ◽  
Prostacyclin Synthesis ◽  
Control Study

Abstract: Cyclooxygenase-2 (COX-2) and prostacyclin synthase (PGIS) are enzymes involved in prostaglandin and prostacyclin synthesis, which have been linked to cardiovascular disease risk. We hypothesized that genetic variations altering the function of these enzymes would modify the risk of myocardial infarction (MI).: In a Chinese case control study of MI patients (n=356) and healthy controls (n=350), we investigated the roles of polymorphisms in the PGIS gene (: The CC genotype of: The CC genotype ofClin Chem Lab Med 2009;47:347–52.

scholarly journals Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Hangjun Ke ◽  
Joanne M. Morrisey ◽  
Shiwei Qu ◽  
Oraphin Chantarasriwong ◽  
Michael W. Mather ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Morphological Changes ◽  
Biological Activities ◽  
Hek293 Cells ◽  
Therapeutic Window ◽  
Malaria Parasites ◽  
Content Type ◽  
Lead Compounds ◽  
Antimalarial Agents ◽  
Transport Chain

ABSTRACT Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ∼10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

scholarly journals The Medicinal Timber Canarium patentinervium Miq. (Burseraceae Kunth.) Is an Anti-Inflammatory Bioresource of Dual Inhibitors of Cyclooxygenase (COX) and 5-Lipoxygenase (5-LOX)

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
R. Mogana ◽  
K. Teng-Jin ◽  
C. Wiart
Keyword(s):  
Inflammatory Diseases ◽  
Ethanolic Extract ◽  
Ethanol Extract ◽  
Frap Assay ◽  
Dual Inhibitor ◽  
Lead Compounds ◽  
Dual Inhibitors ◽  
Cox 2 ◽  
Cox 1

The barks and leaves extracts of Canarium patentinervium Miq. (Burseraceae Kunth.) were investigated for cyclooxygenase (COX) and 5-lipoxygenase (LOX) inhibition via in vitro models. The corresponding antioxidative power of the plant extract was also tested via nonenzyme and enzyme in vitro assays. The ethanolic extract of leaves inhibited the enzymatic activity of 5-LOX, COX-1, and COX-2 with IC50 equal to 49.66±0.02 μg/mL, 0.60±0.01 μg/mL, and 1.07±0.01 μg/mL, respectively, with selective COX-2 activity noted in ethanolic extract of barks with COX-1/COX-2 ratio of 1.22. The ethanol extract of barks confronted oxidation in the ABTS, DPPH, and FRAP assay with EC50 values equal to 0.93±0.01 μg/mL, 2.33±0.02 μg/mL, and 67.00±0.32 μg/mL, respectively, while the ethanol extract of leaves confronted oxidation in β-carotene bleaching assay and superoxide dismutase (SOD) assay with EC50 value of 6.04±0.02 μg/mL and IC50 value of 3.05±0.01 μg/mL. The ethanol extract acts as a dual inhibitor of LOX and COX enzymes with potent antioxidant capacity. The clinical significance of these data is quite clear that they support a role for Canarium patentinervium Miq. (Burseraceae Kunth.) as a source of lead compounds in the management of inflammatory diseases.

scholarly journals Novel Series of Methyl 3-(Substituted Benzoyl)-7-Substituted-2-Phenylindolizine-1-Carboxylates as Promising Anti-Inflammatory Agents: Molecular Modeling Studies

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 661 ◽  
Author(s):  
Venugopala ◽  
Al-Attraqchi ◽  
Tratrat ◽  
Nayak ◽  
Morsy ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Therapeutic Agents ◽  
Cox Inhibitors ◽  
Lead Compounds ◽  
Important Target ◽  
Pharmacokinetic Properties ◽  
Molecular Modeling Studies ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors

The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity. Compound 4e was identified as the most active compound of the series with an IC50 of 6.71 M, which is comparable to the IC50 of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID). Molecular modeling and crystallographic studies were conducted to further characterize the compounds and gain better understanding of the binding interactions between the compounds and the residues at the active site of the COX-2 enzyme. The pharmacokinetic properties and potential toxic effects were predicted for all the synthesized compounds, which indicated good drug-like properties. Thus, these synthesized compounds can be considered as potential lead compounds for developing effective anti-inflammatory therapeutic agents.

scholarly journals Development and Validation of a High-Throughput Screen for Inhibitors of SARS CoV and Its Application in Screening of a 100,000-Compound Library

2006 ◽  
Vol 12 (1) ◽  
pp. 33-40 ◽  
Author(s):  
William E. Severson ◽  
Nice Shindo ◽  
Mindy Sosa ◽  
Thomas Fletcher ◽  
E. Lucile White ◽  
...  
Keyword(s):  
High Throughput ◽  
Cytopathic Effect ◽  
High Throughput Screen ◽  
Compound Library ◽  
Hit Rate ◽  
Compound Libraries ◽  
Potential Inhibitors ◽  
Development And Validation ◽  
Large Compound

The authors have developed a high-throughput screen (HTS) that allows for the identification of potential inhibitors of the severe acute respiratory syndrome coronavirus (SARS CoV) from large compound libraries. The luminescent-based assay measures the inhibition of SARS CoV–induced cytopathic effect (CPE) in Vero E6 cells. The assay was validated in 96-well plates in a BSL3 containment facility. The assay is sensitive and robust, with Z values > 0.6, signal to background (S/B) > 16, and signal to noise (S/N) > 3. The assay was further validated with 2 different diversity sets of compounds against the SARS CoV. The “hit” rate for both libraries was approximately 0.01%. The validated HTS assay was then employed to screen a 100,000-compound library against SARS CoV. The hit rate for the library in a single-dose format was determined to be approximately 0.8%. Screening of the 3 libraries resulted in the identification of several novel compounds that effectively inhibited the CPE of SARS CoV in vitro—compounds which will serve as excellent lead candidates for further evaluation. At a 10-μM concentration, 3 compounds with selective indexes (SI50) of > 53 were discovered.

Chylomicron-remnant-like particles modify production of vasoactive mediators by endothelial cells

2004 ◽  
Vol 32 (1) ◽  
pp. 110-112 ◽  
Author(s):  
M. Evans ◽  
Y. Berhane ◽  
K.M. Botham ◽  
J. Elliott ◽  
C.P.D. Wheeler-Jones
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
Endothelial Cell Function ◽  
Cell Dysfunction ◽  
Vasoactive Mediators ◽  
Prostanoid Production ◽  
Cox 2 ◽  
Chylomicron Remnants ◽  
Oxide Synthase ◽  
Prostacyclin Synthesis

Endothelial-cell dysfunction is a critical initiating event in the pathogenesis of atherosclerosis. Although there is evidence to suggest that chylomicron remnants (CMRs), lipoproteins derived from the diet, influence endothelial-cell function to generate a pro-atherogenic phenotype, the mechanisms involved remain undefined. We have examined the effects of CMR-like particles (CMR-LPs) on human endothelial-cell function, focusing on the cyclo-oxygenase (COX) and nitric oxide synthase (NOS) pathways. CMR-LPs strongly enhanced the expression of the inducible cyclo-oxygenase COX-2 and increased prostacyclin synthesis in a biphasic manner. Studies with the COX-2-selective inhibitor NS-398 confirmed the COX-2 dependency of the later increase in prostanoid production. Pre-incubation with CMR-LPs reduced basal and thrombin-stimulated cGMP generation, whereas expression of endothelial NOS was not modified by remnant treatment.

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